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Progr. expo Tumor Res., vol., 10, pp. 163-237 (Karger, Basel/New York 1968)
Bio-Research Institute, Cambridge, Massachusetts
The Syrian Golden Hamster
in Chemical Carcinogenesis Research 1
F. Homburger
Contents
164
164
166
175
177
185
186
193
193
196
197
199
203
203
203
214
214
214
214
214
214
215
220
221
223
226
1 This work was supported by Public Health Service General Research Support
Grant No. S01-FR-05525 from the Division of Research Facilities and Resources;
Research Grant No. CA-04869 from the National Cancer Institute; and contributions
from the Virginia and D. K. Ludwig Foundation and Bio-Research Consultants, Inc.
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Author's Note .........................................................
Introduction.. ........ . ... . ... ... . ... . ... ... . ... ... . .. . ... . ... . ... . ... .
Skin..................................................................
Flank Organ...........................................................
Cheek Pouch ..........................................................
Oral Cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Respiratory Tract ......................................................
Gastrointestinal Tract... . . ... ... . . . . . ... ... . ... . .. . .. . ... . .. . . .. . . .. . ...
1. Submaxillary glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Stomach and intestines ............................................
3. Gallbladder, biliary tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Liver ...........................................................
Urinary Tract.. . . .. . ... . . .. . .. . ... . ... ... . .. . ... .. . .. . . ... . .. . . ... . ... .
1. Kidney ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Urinary bladder ..................................................
Male Genital Tract .....................................................
1. Testes...........................................................
2. Prostate .........................................................
3. Epididymis ......................................................
Female Genital Tract ...................................................
1. Uterus ..........................................................
2. Uterine cervix .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Breast Gland ..........................................................
Endocrine Glands......................................................
Subcutaneous Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
164
HOMBURGER
Author's Note
This review employs the technique suggested by HANS SELYE in his book on The
Mast Cells [206]. Accordingly, it 'facilitates fact-finding and strictly separates the objective,
concise report of previously published data from the author's evaluation of them.'
In this method the reviewer's summaries and evaluations of published material are
printed in large type, while his abstracts made from published papers are grouped separately, in chronological order under each subject, and printed in petit type.
The literature search for these reviews was based on the hamster bibliographies of
MAGALHAES 2 and of KITTEL3 and on the Index Medicus through 1966.
For the reader's convenience in locating cross references, the page numbers are
indicated in parentheses in the list of references at the end of the chapter.
Throughout this review, the abbreviations in the extreme left column will be used
for chemical carcinogens. Chemical Abstracts nomenclarure appears in parentheses.
BP
DBP
DMBA
DBA
BA
MC
NQO
2-A
DENA
DMNA
AAF
3,4-Benzpyrene
3, 4, 9, 10-Dibenzpyrene
9, 10- Dimethyl-I, 2benzanthracene
1, 2, 5, 6-Dibenzanthracene
1,2-Benzanthracene
20-Methylcholanthrene
4-Nitroquinoline-N-oxide
2-Anthramine
Diethylnitrosamine
Dimethylnitrosamine
2-Acetylaminofluorene
(Benzo[a]pyrene)
(Benz[rst]pentaphene)
(Benz[a]anthracene, 7, 12dimethyl-)
(Dibenz[a,h]anthracene)
(Benz[a ]anthracene)
(Cholanthrene,3-methyl-)
(Quinoline, 4-nitro, l-oxide-)
(2-Anthramine)
(Diethylamine, N-nitroso-)
(Dimethylamine, N-nitroso-)
(Acetamide, N-fluorene-2-yl-)
Introduction
In many respects the Syrian hamster responds to chemical carcinogens much as do rats or mice. That hamsters respond with tumor
formation to carcinogens was discovered quite soon after these
rodents were first brought into the laboratory.
2 MAGALHAES, H.: Bibliography on the Golden Syrian Hamster, 1931-1963, Department of Biology, Bucknell University, Lewisburg, Pa. (1965).
3 KITTEL, R.: Z. Versuchstierk. 8: 1-166 (1966).
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Adler [1]: The Syrian golden hamster, Cricetus auratus, was taken by Professor
Aharoni of the Department of Zoology, Hebrew University of Jerusalem, in 1930 to Dr. S.
Adler of the Department of Parasitology of the same institution for studies in kala azar.
The animals originally taken to the laboratory were one male and two females, all littermates, from which have descended all known Syrian hamster specimens used in European
and American research laboratories.
Gye & Foulds [79]: This is the first injection of 0.4% solution of BP in lard, given
subcutaneously to two males. The dose was 0.2cc given at weekly intervals for four weeks;
the fifth dose was administered after an intermission of six weeks. The injection site was
The Syrian Golden Hamster in Chemical Carcinogenesis Research
165
In other respects there are special types of response found in
Syrian hamsters, as seen below:
Skin: Mast-cell morphology, chemistry and response to carcinogens differ from those in other rodents. Promoting agents, such as
croton oil, fail to work in hamsters. Hamster skin has a marked
tendency to melanoma formation and the development of dermal
melanocytomas follows the application of certain carcinogens.
Flank organ: A specialized structure characterized by large sebaceous
glands resistant to carcinogens and by coarse hair with prolonged
growth phase; sensitive to systemic tumor induction by estrogenandrogen mixtures.
Cheek pouch: Permits comparison in same animal between epithelium with and without pilosebaceous apparatus. Cocarcinogens
function in cheek pouch (in contrast to skin).
Respiratory tract: Marked resistance to pulmonary infections and
great tolerance to intratracheal instillations. Tracheobronchial tract
and anterior and posterior nasal cavity (ethmoidal region) form tumors
following systemic diethylnitrosamine administration. Bronchial
neoplasia follows tracheal carcinogen instillation.
Gastrointestinal tract: Uniquely high incidence of spontaneous
gastrointestinal tumors reported from some hamster colonies. Oral
administration of carcinogens produces gastrointestinal cancers.
Biliary tract appears responsive to carcinogens.
Liver: In some respects hamster metabolism of diazo-dyes is closer
to human metabolism than that of the rat.
Kidney: Uniquely responsive to estrogen tumor induction. Possibly the only experimental model of human renal cancer.
Genital tract-male: Prostate responds to estrogen with squamous
metaplasia. Leiomyomas of epididymis form with estrogen-androgen
treatment.
Genital tract-female: Cystic hyperplasia and also leiomyomas producible in uterus with estrogen. Cancer of cervix producible with
topical application of estrogens.
Breast: Apparently unresponsive to estrogen stimulation, yet
susceptible to oral methylcholanthrene and urethan.
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always the nape of the neck. Of the two spindle cell sarcomas that developed, one was
transplantable.
Schinz & Fritz-Niggli [201]: A total of 40 mg of BP dissolved in 70% carbowaxwater was applied in drops to the skin of hamsters weekly over a period of 14 months.
This resulted in cancer of the basal layer of the epithelium 16 months after the initial
treatment. Conclusion: The hamster is susceptible to benzpyrene carcinogenesis.
166
HOMBURGER
Pituitary: Prone to adenoma induction by estrogens.
Tf?yroid: Readily susceptible to tumor induction by nutritional
means.
Subcutaneous tissue and mesencf?yme: Subcutaneously induced and
transplanted tumors metastasize readily to distant organs. Fibroblasts show malignant transformation, as judged by cytologic criteria,
far more quickly than reported in other rodents. Stromal tissue of
parenchymatous organs forms less fibrosis upon local injection of
carcinogens than observed in mice and rats-hence, a greater opportunity for carcinoma (adenoma) induction by topical injection into
organs.
Hamster skin possesses the ability to form melanotic tumors in
response to direct application to the skin of certain carcinogens,
especially DMBA, BA, NQO and urethane. Similar melanotic tumors
have been produced by feeding or injecting urethane. Newborn
animals were especially sensitive to the production of melanotic
tumors by the injection of as little as 100 {-lg of DMBA.
Other carcinogens, such as BP, DBA, Me and 2-anthramine, produce
hyperplasia, papillomas, keratoacanthomas, basal cell tumors and
squamous cell tumors.
In hamsters there exist spontaneous malignant melanomas with
junctional changes likening these tumors to human melanomas. On
the other hand, chemically induced melanotic lesions in these animals
are devoid of junctional changes and may be considered the counterpart of human blue nevi, although on occasion such induced hamster
lesions have been transplanted and hence shown to be malignant.
Chemical induction of melanotic lesions in hamster skin has
permitted studies of the cytogenesis of these lesions. In cream colored
hamsters the perifollicular melanocytes are practically absent, and
in the agouti and white variety they are abundant, although normally
amelanotic in the white animals. Hence, the cream colored hamster
fails to form melanotic lesions upon application of chemical carcinogens, while the other varieties respond readily with melanotic
tumors.
Surprisingly, croton oil and Tweens, whenever tested in hamsters,
failed to have cocarcinogenic effects when applied to skin after various
initiators.
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Skin
The Syrian Golden Hamster in Chemical Carcinogenesis Research
167
Bock [24]: This is a study on the skin thicknesses and differences of penetration of
three carcinogens, DMBA, BP and Me. The hamster skin thickness (31.7 mgJcm2)
ranges closely to that of the mouse (26.2) and that of the head of the inner surface of the
rabbit ear (54.9); the rat, guinea pig and man have much heavier weights. In carcinogen
penetration, the hamster was between mouse and rabbit for BP and MC and somewhat
lower than the mouse but a little higher than the rabbit for DMBA. The author's conclusion is that differences in skin penetration may be a cause of species differences in skin
carcinogenesis. In addition, other factors modifying skin carcinogenesis include the
nature of the solvent, concentration of hydrocarbon, state of hair growth and species
and strain of animals used.
Bock & Burnham [25]: The influence of strain and species upon the uptake and retention of hydrocarbon by the skin of rodents was studied. Maximum skin levels of hydrocarbon were found two hours after 'painting'. The maximum levels were not affected by
hair growth, although the hydrocarbon was cleared somewhat more rapidly from mouse
skin in which the hair was growing.... Among 28 mouse stocks painted with 1% BP,
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Peculiarities in the dermal mast-cell response to carcinogen
application constitute another species-specific response of hamsters.
While there is an immediate inflammatory leukocytic reaction to the
application of carcinogens which is more pronounced than that seen
in the skin of other rodents, there is only a moderate mast-cell exudation below the hyperplastic epidermis. In the hamster, these mast
cells are less granulated than those of other species under similar
conditions and are devoid of 5-hydroxytryptamine.
In spite of this chemical and morphological difference of the
mast-cell response and the exceptional intensity of the leukocytic
reaction, the tumor susceptibility of hamster skin to DMBA is comparable to that of rabbits and mice, and greater than that of rats
and guinea pigs and ground squirrels. These species differences in
skin susceptibility to carcinogens do not correlate with skin thickness,
but may be more closely correlated with the rate of uptake of carcinogens in the skins. In all probability, however, more subtle chemical
differences govern the species-specific variations of skin susceptibility.
It is possible in the hamster to make direct comparison between
the susceptibility of epidermis with its appendages to chemical
carcinogenesis and the susceptibility of the cheek pouch, another
squamous stratified epithelium with only two minor glands. This has
been studied with cheek pouches left in situ as well as with cheek
pouches exteriorized into the skin (for abstracts see also under Cheek
pouch). While the penetration rate of fluorescent substances is about
the same in both epidermis and cheek pouch epithelium, the best
evidence suggests that skin is more susceptible to carcinogenesis and
the inference may be drawn that skin cancers arise most readily in the
dermal appendages.
HOMBURGER
the skin level ranged from 10.2 pgm for ICR Swiss to 33.7 pgm/g for DBA/1. Reciprocal
F-1 hybrids of a 'high' and a 'low' strain behaved like the low parental stock. In six of the
28 stocks, higher levels were attained in male mice than in female mice of the same strain .
. .. In contrast to the values found in mouse skin, BP levels in treated guinea pig skin
reached a maximum of only 2.9 pgm/g. Rabbits and hamsters were intermediate between
mice and guinea pigs. These observations may explain some of the species differences in
skin carcinogenesis.
Chieco-Bianchi et al. [34]: In contrast to observations made in mice where there is
intensive mast-cell infiltration after painting with DMBA, and peculiar fluorescence
typical of 5-hydroxytryptamine as well as other evidence of 5-hydroxytryptamine concentration of mast cells in hamsters, this phenomenon did not occur, although there was
mast-cell infiltration. The mast cells appeared smaller and less granulated than normal
mast cells and were located mostly beneath the hyperplastic epidermis. Neither determination of hydroxytryptamine skin level nor fluorescence studies showed any increase in
this substance. These findings indicate that no 5-hydroxytryptamine production occurs
in normal skin mast cells of hamsters or in mast cells appearing in the dermis during
carcinogenic treatment in these animals. This questions seriously the role of this amine
in the mast-cell reaction developing during the course of chemical skin carcinogenesis.
Della Porta et al. [43]: A single application of DMBA (1 % solution in liquid petrolatum) produced melanotic lesions resembling the cellular blue nevi of man. There
was no resemblance to malignant melanocarcinoma of human skin because of complete
absence of junctional changes in the epidermis. There was some striking resemblance to
cutaneous neurofibromas of man. The multiple applications of DMBA caused squamous
cell papillomas as in other species. Croton oil, which was not carcinogenic when given
alone, had no cocarcinogenic promoting effects in the hamster.
Della Porta et al. [44]: The carcinogenic action of DMBA, with and without croton
oil, has been studied on the skin of the Syrian golden hamster. Qualitatively different
results have been obtained with variation in dosage of carcinogen. With repeated applications of the carcinogenic hydrocarbon the usual pattern of papilloma and squamous-cell
carcinoma induction has been observed. With only a single application of this carcinogen,
with or without croton oil, cutaneous melanotic tumors were induced. Thus, in a total of
nine hamsters, eighteen pigmented lesions were observed. Of these melanotic lesions,
one has thus far been transplanted successfully.
Dontemvill & Mohr [54]: Forty-two-day-old male hamsters received 0.5 cc of an 0.5%
oil solution of BP by stomach tube twice weekly. Another group received, three times
weekly, 2% BP in sesame oil in a spray introduced into the oral cavity; in a week each
animal received 2.5 mg BP. Findings: 93 animals which received BP by stomach tube
showed 17 papillomata and 2 carcinomas of the forestomach and a papillary tumor of the
upper trachea. Forty-five hamsters treated with oil spray had 15 papillomas, 11 carcinomas
(predominantly of the skin of the face and the lips), 16 papillomas of the trachea (2 of
which had infiltrative proliferation), and 23 papillomas and 2 carcinomas of the forestomach. In nearly all of the animals there were variable degrees of basal cell hyperplasia and
moderate metaplasia which was definitely benign. This study shows differences in the
susceptibility of the skin, oral mucosa, tracheal epithelium, etc. The greatest sensitivity
was in the outer skin. Trachea and stomach were less sensitive, whereas the oral cavity
and the cheek pouch showed no tumors at all.
Fortner [70]: This paper reports on diffuse epithelial changes resembling malignant
melanoma arising at multiple sites and lymphocytic leukemia which are induced in
Syrian golden hamsters following the subcutaneous injection of a minced suspension of
tissue obtained from animals afflicted with these diseases. It is implied that the inciting
agent of these entities may be filterable virus.
GHADIALLY [74]: Forty male hamsters and mice were given repeated paintings of a
1 % solution of DMBA in a mixture ofequal parts of anhydrous lanoline and liquid paraffin.
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169
No organic solvents were used. All animals were painted once a week with the carcinogen
until half of them had developed tumors (8 weeks for the mice; 9 weeks for the hamsters).
Thereafter, the animals bearing tumors were painted sporadically, or not at all. Animals
without tumors continued to receive weekly painting until they formed tumors, after
which histology was done. Tumors occurred in mice and hamsters not only at the application site, but also around the chin and the chest wall, probably due to spreading of the
carcinogen by the animals in the process of grooming. There were papillomas and keratoacanthomas, several of which regressed. There were also some multiple melanotic tumors
and some sebaceous adenomas in the hamsters. Pigmented tumors were similar to those
described by DELLA PORTA et al. Lesions morphologically resembling the keratoacanthoma
of man and previously experimentally induced in rabbits have now been produced in the
hamster and in the mouse by DMBA. Their biological behavior is essentially the same
in all species, except that there is more of a tendency toward continued growth of this
lesion in the hamster and the mouse than was observed in the rabbit.
Ghadially & Barker [75]: This is a paper studying the histogenesis of DMBA-induced
melanotic tumors of the hamster. DELLA PORTA and others have suggested that tumors
induced in the hamster are equivalent to blue nevi in man and probably arise in similar
fashion. FORTNER AND ALLEN claim to have observed junctional activity and suggest
that these tumors are the counterpart of malignant human melanoma. In contrast to this,
it is demonstrated in this paper that the nevi or melanotic tumors induced in the hamster
by application of chemical carcinogens arise from a perifollicular network of melanocytes
not found in rabbits or mice. This provides an explanation for the histogenesis of the
melanotic tumors in the hamster and differentiates them from all other melanotic tumors.
It explains why hamsters are so much more prone to the development of melanomas
during cutaneous chemical carcinogenesis than mice or rabbits. The costo-vertebral spot
is rich in sebaceous glands and is resistant to local application of a carcinogen. This is
so because in this spot the sebaceous glands are not destroyed by the carcinogen, as
happens in the surrounding skin. This possibly can be attributed to the fact that coarse
hair with a long growth phase occurs in the costo-vertebral spot, while fine hair showing
a well-defined resting phase occurs in the surrounding skin.
Ghadially et al. [77]: This paper is intended to study the effects of various types of
mechanical trauma upon the behavior of the melanotic tumors induced in brown and
white hamsters with DMBA. All the procedures used, namely, needle pricking, cutting
with a knife and everting the sectioned tumor failed to change the behavior of the growth
and failed to induce truly malignant transformation. The only positive finding was an
increased production of melanin in some of the injured hypomelanotic melanomas. It
was also noted that injured as well as uninjured melanomas induced with DMBA in the
hamster could occasionally regress. This was particularly true of lesions measuring less
than 1 mm.
Illman & Ghadially [98]: This is an experiment designed to study the differences in
tumor production by DMBA in brown, white and cream hamsters-24 brown, 24 white
and 24 cream-aged 4 to 6 months and weighing about 90 g. There were equal numbers
of males and females. The hair was clipped and a 2% solution of DMBA applied with
a Camel Hair brush to the skin immediately surrounding the left costo-vertebral spot.
This was done once a week for a period of 22 weeks and observed for a further period of
9 weeks. The number of melanotic tumors seen in each animal was recorded at weekly
intervals during painting and at 2- or 3-week intervals during the later stages of the
experiment. Many melanotic tumors developed in the brown and white varieties, but
none were seen in the cream animals. Melanotic tumors developed earlier and in greater
numbers in the brown than in the white hamsters. Tumors in the white animals increased
in size more rapidly and this group ultimately showed fewer but much larger tumors.
There were many more melanotic tumors in females than in males. Besides melanotic
tumors, there were many keratoacanthomas and some squamous cell carcinomas in
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The Syrian Golden Hamster in Chemical Carcinogenesis Research
HOMBURGER
almost all of the brown and white hamsters, but in less than half of the animals in the
cream variety. In the latter, these tumors appeared six weeks later than similar tumors in
the brown and white animals. The reasons for the differences in this susceptibility to
carcinogenesis in white, brown and cream animals are analyzed: While the network of
melanocytes surrounding the pilosebaceous follicle in the small pigmented spots of the
skin are seen less frequently in the cream variety, none at all were seen in the white
variety, and yet more melanotic tumors were produced. It seems that in the case of the
white hamster, many melanocytic networks may exist but are not demonstrable because
they are amelanotic. It would appear that in the case of the cream variety, the paucity
of the melanocytic network in the skin and a genetic or strain resistance to the action
of carcinogen are responsible for the failure to produce melanotic tumors. Not only were
there no melanotic tumors, but there also was a considerable delay in the production of
epithelial tumors and a markedly poorer final tumor yield. It is noted that earlier experiments on skin carcinogenesis in the Syrian hamster usually employed the brown or
golden variety. This is the first paper calling attention to the genetic differences in the
hamster's response to chemical carcinogenesis.
Kriegel [125]: This is a careful study comparing single applications of DMBA with
multiple applications in various animals, including the golden hamster. The report deals
with 38 golden hamsters of both sexes weighing 70-90 g and aged 10-12 weeks. Application was made of an 0.5% DMBA-acetone solution to a 3 cm 2 field of skin in the center
back. Three drops or 0.25 mg of DMBA represented a single application. Both fluorescence microscopy and light microscopy were carried out. It was found that DMBA
initially caused in the hamster a marked leukocytic infiltration, described as more massive
than in any of the other animal species tested. In the earliest case of twice-week applications of D MBA, tumors were found 85 days after the beginning of the treatment, whereas
with single applications, they occurred after 120 days. In any case, 100% of the animals
eventually showed tumors. Comparisons of the rate of tumor development were made
between hamster, rabbit, mouse, guinea pig, rat and fowl; the incidence curves for the
rabbit, mouse and hamster were very close together, with the rat showing a slower
tumor development and the guinea pig showing resistance. In the fowl also, no tumors
developed. The histopathology of the developing tumors in mice and hamsters was quite
comparable, and there was definite evidence of multicentric origin of the induced tumors.
Lee et al. [126]: This paper reports work done to test the effectiveness of DMBA
when given in a single injection to the newborn hamster, rat and mouse. Carcinogen was
administered in tri-N-caprylin (Trioctanoin) from Eastman Organic Chemicals, New
York. The concentrations of DMBA were such that the amount of solvent was 0.05 m!.
Doses of 1000, 200 and 100 p,y produced subcutaneous sarcomas and dermal melanocytomas. Additionally, a slight acceleration of the appearance of malignant lymphomas
was found. In contrast, in the Swiss and AKR strains of mice, there were tumors distant
from the application site, namely, lymphomas and lung adenomas. In the case of Lewis
rats, there were essentially local reactions. The sarcomas and the melanocytomas induced
by this procedure were similar in appearance and microscopy to those induced in adult
hamsters.
Levy [127]: This is a discussion of the similarities and differences between the skin and
oral mucosa; it emphasizes systemic factors which influence carcinogenesis at these sites.
Maltoni& Prodi [129]: This is a study on 26 hamsters which received 0.3% ofDMBA
twice a week. First tumors appeared after 53 days, and by the 75th day tumors (mostly
multiple) had occurred in all animals. Thus, the hamster skin is the most sensitive subject
for DMBA carcinogenesis and compares favorably with mouse, rabbit, rat, fowl and
guinea pig in descending order. Not only was the time of latency short, but there were
multiple tumors in the majority of the animals.
Mishima & Oboler [139]: Histochemical study of the skin defines three distinct melanocyte systems: 1. functional melanocytic melanocytes, which are the enzymically active
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melanocytes in the hair bulb and in occasional perifollicular networks; 2. potentially or
minimally functional amelanotic melanocytes with premelanin-positive reaction upon
stimulation by ultraviolet radiation in the outer sheath layer of the hair follicle below
the melanogenic level and diffusely in the dermis; 3. disfunctional amelanotic melanocytes
of epidermis which do not become DOPA-positive even after stimulation by ultraviolet
rays, but do synthesize varied plate-like cytoplasmic granules. The observations on
DMBA application suggest that this carcinogen selectively produces in the hamster neoplastic growth in potentially functional amelanotic dermal melanocytes, but not in the
disfunctional amelanotic melanocytes of the junctional layer. On the other hand, sodium
taurocholate-induced melanomas and spontaneous melanomas (FORTNER [69]), occur
exclusively in the disfunctional amelanotic melanocyte system (system 3).
Nakai & Rappaport [149]: Carcinogen-induced melanotic tumors of the Syrian
hamster differ morphologically and biologically from the spontaneous malignant melanomas of the same species. They are composed of dermal melanocytes, show no junctional
changes and resemble cellular blue nevi or pigmented neurofibromas. They grow slowly
and metastasize rarely. They can be induced in the golden hamster, in which malignant
melanoma occurs spontaneously, and in the white hamster, in which malignant melanomas
have never been reported. These carcinogen-induced melanotic tumors are derived from
cells that can be stimulated to grow and form melanin pigment by the topical application
of DMBA and by the oral administration of urethan. In contrast, epidermal melanocytes
of the hamsters do not respond with increased melanin production or with cellular
proliferation to these carcinogens. Neural elements, particularly Schwannian cells, are
abundant in the early perifollicular tumors of both hamsters, that is, white and pigmented.
Occasional melanocytes containing the characteristic pigment granules were demonstrated
within small fascicles electron microscopically. Thus, the carcinogen-induced melanotic
tumors are of endoneural and probably Schwannian cell origin, and it is concluded that
the neuroectodermal mesenchyme of small dermal nerves is susceptible to the melanogenic
and growth-inducing effects of DMBA. The epidermal melanocytes, in contrast, in the
Syrian hamster are resistant to the carcinogenic effect of DMBA.
Pietra & Shubik [155]: Urethan was given as an 0.2% solution in drinking water to
female and male Syrian golden hamsters. It caused in the males a high incidence of
melanotic tumors similar to those elicited in this species by DMBA. In both sexes, a high
incidence of papilloma of the forestomach was also observed. Cutaneous application of
20% urethan failed to show a tumorigenic effect. (This appears to be in contrast with
other observations indicating that the painting of urethan did cause skin tumors [181]).
Prodi & Maltoni [158]: The changes which take place in the dermis during skin
treatment with oncogenic hydrocarbons and co-carcinogenic irritating substances were
comparatively studied in various animal species (mouse, rabbit, rat, guinea pig, hamster) .
. .. The alterations induced in the extracellular structures of the dermis by both oncogenic
and irritating substances are qualitatively analogous in different animal species.... During
the treatment the dermis collagen fibres are metachromatically stained; this peculiar
behaviour takes place first in the upper layers, then in lower ones. Such staining properties
precede the morphological changes of the fibres and become more marked with the
progressing of these changes. ... The morphologic and staining modifications of the
fibres are proportional to the proliferation of the overlying epithelium, whether this be
provoked by either oncogenic or irritating substances. These changes are more evident
in correspondence to the areas of higher epidermic proliferation .... It is concluded that
the same substance promotes in different animal species a different degree of dermal
alterations, in relation to the different epidermic responses .... In the rabbit, besides the
above described changes, the appearance of interfibrillar chromotrope substances during
the treatment with oncogenic agents as observed in previous experiments, is confirmed;
such appearance was not observed during the treatment with the irritating substances
used.
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The Syrian Golden Hamster in Chemical Carcinogenesis Research
HOMBURGER
Prodi & Maltoni [160]: This is a brief review of the diphasic concept of cocarcinogenesis and carcinogenesis under various experimental conditions. Experimental studies
were done on the effect of croton oil upon skin carcinogenesis with DMBA as an initiator.
There were very small animal groups, the first consisting of two hamsters treated with
0.3% acetone solution ofDMBA, 2 applications 3 days apart; the second group, 4 animals
treated only with croton oil in a 2.5% olive oil solution twice a week for the duration
of the experiment; the third group, 10 animals initiated with DMBA as group 1, and
16 days after beginning of croton oil treatment, as in group 2. There was a rather large
mortality rate. In this experiment, no malignant tumors were actually induced; therefore,
there was a failure of carcinogenesis and cocarcinogenesis. It was noted that the prolonged
treatment with croton oil alone showed an epithelial hyperplasia in the hamster which
was much milder than in the mouse, and the possible explanation of failure of cocarcinogenesis is this less pronounced irritant effect of croton oil.
Prodi & Maltoni [159]: The histochemical properties and structural characteristics
in different animal species subjected to skin treatment with DMBA have been studied. In
all the animals the dermis shows new staining characteristics in relation to both Mallory
stain and silver impregnation, undergoing a process of structural rearrangement which
leads to a much more irregular and rarefied organization. Such alterations are progressing
from the uppermost to the innermost layers and are proportional to the degree of hyperplasia of the overlying epithelium. At the onset of tumors in the rabbit, hamster and rat,
these alterations are progressive and extended to the whole dermis; in the rat and guinea
pig they soon enter a stationary stage where their limits are fixed by a barrier of normal
dermis.
Quevedo [161]: The relation of melanocytes to melanoma formation has been studied
and reviewed. It is shown that certain melanocytic tumors may arise from melanocytes
at the dermoepidermal junction, in the dermis and hair follicles. The mechanisms which
trigger the malignant transformation of melanocytes are obscure. Attempts to relate the
gross pigmentation of primary and secondary melanocytic tumors to their potential
malignancy are controversial. Similarly, the importance of skin and hair coloration in
skin carcinogenesis remains unsettled.
Quevedo et al. [162]: In golden (agouti) hamsters, pigmented melanocytes of the
general body skin are restricted to hair bulbs and occasional networks surrounding
pilosebaceous units [75]. The dermal melanocyte networks are associated with the connective tissue sheaths of hair follicles at approximately the level of the sebaceous glands,
and the number of visible networks increases with advancing age. Pigmented melanocytes
are lacking in the general body skin of white hamsters [98, 163]. In the present study,
white and golden hamsters were repeatedly painted with a 1 % croton oil-in-acetone
solution. Numerous perifollicular networks of pigmented melanocytes appeared in both
varieties within 15 weeks. However, despite continuing treatment for 26 weeks, melanocyte networks retained their structural integrity, suggesting that the principal action of
croton oil is to increase melanin synthesis without significantly affecting melanocyte
proliferation [211]. By contrast, 3 applications of DMBA (1% in mineral oil) elicited
melanotic tumors in both white and agouti hamsters; by 26 weeks, occasional tumors
measured 11 mm in diameter. In agreement with GHADIALLY AND BARKER (Ibid), these
tumors were found to arise within perifollicular melanocyte networks, and with increasing
size involve numerous hair follicles. Thus, DMBA stimulates increased division and
migration of dermal melanocytes as well as increased melanin synthesis.
Quevedo et al. [163]: In this paper, the induction of melanotic tumors by DMBA is
reported in 10 male and 10 female randombred white hamsters, 4 months old, treated
once weekly for three consecutive weeks with a 1% solution of DMBA in mineral oil
(without knowledge of the work of ILLMAN AND GHADIALLY [98]). This was done on
the shaved skin and it is estimated that approximately 200-300y of DMBA were applied
each time. Pigmented nodules, as in SHUBIK'S case [211], were observed. It was speculated
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that melanotic tumors in white hamsters are derived from a system of amelanotic perifollicular melanocytes.
Rappaport et 01. [165]: This is a review article on the melanotic tumor induced by
DMBA; it gives in rather concise form the same conclusions as several other papers by
the same authors.
Rappaport et 01. [166]: Melanotic tumors resembling cellular blue nevi of man were
induced in the Syrian white hamster by single and multiple applications of DMBA. They
resemble the tumors produced under similar experimental conditions in the golden
hamster. There is great variability of the intensity of pigmentation. None of these tumors
metastasized. One of the poorly pigmented tumors was transplanted into golden and
white hamsters. One of the transplants gave rise to metastases to lymph nodes, lungs and
kidneys. It is not stated whether the transplant metastasized in the white or in the golden
hamster. The capacity to produce pigment was retained in the transplanted tumors. The
study confirms the previous observation by the same authors that cutaneous application
of a single dose of DMBA to Syrian hamsters induces a high incidence of melanotic
tumors which differ morphologically and biologically from the melanomas known to
occur spontaneously in the Syrian golden hamster. In a footnote, the authors point out
that it has been shown by ILLMAN AND GHADIALLY [98] that the skin of white hamsters
is devoid of the perifollicular collection of pigmented melanocytes which are found
in the golden hamster around some of the pilosebaceous follicles and using repeated
applications of DMBA, these authors were able to induce tumors identical with those
described in the present review in the white Syrian hamster, but not in the cream colored
variety.
Riviere et oj. [181]: There were 40 controls of apparently randombred hamsters and
80 experimental animals, about 1 month of age, half males and half females. Urethan was
applied with a brush in a 50% solution in acetone from 1 to 3 times per week on the
previously shaved back. In each painting, approximately 125 mg urethan was applied and
the number of paintings per animal varied from 50 to 105. In the control animals, no
tumors appeared; in the majority of the treated animals, after several weeks, small pigmented areas appeared which transformed themselves into tumors of 0.321 cm average
size. None of these was at the site of the flank organ or on the abdomen; all were in the
painted dorsal area. Three of these tumors were transplanted and grew through the
seventeenth passage. Whereas melanomas have not been produced by urethan in any
other species, the hamster seems to be particularly sensitive to urethan and to melanoma
formation. Urethan given by mouth results in an entirely different picture with no melanoma formation but, rather, prestomach cancers, lymphomas, hemangiosarcomas, pulmonary adenomas, mammary tumors and miscellaneous other malignancies [for references see
226 and 155]. Several authors have failed, however, to produce skin melanomas with
topical treatment, and this is ascribed to the lower doses used. Most of the melanomatous
tumors that developed were not very malignant, although some metastasized. It appears
that the larger the dose, the greater the degree of malignancy.
See Schinz & Fritz-Nigg/i [201, p. 165].
Searle & Woodhouse [205]: 4-Nitroquinoline-N-oxide (NQO) has been found to be a
potent carcinogen for the skin of the golden hamster. Ten animals were treated twice
weekly with 0.5 ml of an 0.5% acetone solution on the shaved dorsal skin. Three animals
died early from an infection; of the remainder,S developed one or more flattened ulcerating growths after 14-36 weeks; these were squamous cell carcinomas and keratoacanthomas. There were two rapidly growing melanomas (this author mentions that GHADIALLY AND BARKER [75] found the melanomas that they induced to be preferentially
located in the costo-vertebral spot). These authors also observed a great avidity of NQO
for -SH groups in various tissues and therefore tested NQO, administering it alternatively
with BP. Under these conditions, NQO strongly inhibited the carcinogenic activity of
the BP.
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HOMBURGER
Sharashidze & Bulusashvili [207]: An 0.1 % benzene solution of DMBA induced cancer
in 100% of the hamsters after 35 to 40 applications, whereas not one case of skin cancer
was observed in the sousliks (eitel/us eitel/us) under similar conditions. No microscopic
differences could be detected between the carcinogen-resistant skin of the ground squirrel
(sousliks) and the sensitive skin of the golden hamster, nor was there any difference in
amino acid content. The content of free SH groups, however, was higher in hamster
skin, as were the ribonuclear proteins. The isoelectric point of these cytoplasmic elements
is pH 3.88 against 4.66 in the sousliks skin. Similar characteristics were found in the
sensitive skin of the A mouse. During carcinogenesis, the free SH groups were reduced
and the isoelectric points of the ribonuclear proteins decreased to 2.62-3.20. Glycogen
appeared in the cells of the sensitive animals. With advancing carcinogenesis, these
changes returned to normal.
Shubik [209]: This is a review article on the author's experience and some of the
literature through 19590n carcinogenesis in the hamster. DMBAinducedmelanotic tumors
in Syrian hamsters after a single application. Feeding or injection of urethan produced
the same tumor. Repeated applications of DMBA produced papillomata and carcinomata,
as did a series of other related carcinogens. Intratracheal DMBA resulted in epidermoid
and adenocarcinomata of the trachea. Generally, tumor induction exaggerates the incidence of the spontaneous tumor pattern existing in a species. In this case, a melanotic
tumor is provoked that does not at all appear spontaneously, or extremely rarely, in the
hamster. (This tumor described by SHUBIK was later observed spontaneously by FORTNER
[70]). Furthermore, it is difficult to distinguish any initiation-promotion sequence such
as is found in rat and mouse carcinogenesis. (These studies started out as an examination
of the co-carcinogenic effect of croton oil which in this instance was not found to be
effective.)
Shubik et al. [210]: Melanotic tumors induced in Syrian golden hamsters by means
of DMBA applied directly to the skin were successfully transplanted to homologous
animals. The transplant resembled the originally induced lesions, but showed a more
pronounced and more irregular cell proliferation. After transplantation the tumor cells
retained their ability to produce large amounts of melanin and fibrillar reticulum.
Shubik etal. [211]: The carcinogens tested wereDMBA, MC, BP, DBA, BA and 2-A; all
were given topically in mineral oil. Cocarcinogens studied after a single application of the
carcinogens were croton oil and Tween 60, both of which were found to be ineffective,
in contrast to all known observations in mice. Melanotic tumors similar to those previously
described were induced with DMBA. Among the other carcinogens tested, only MC gave
rise to a single melanotic tumor. There appears to be a specificity of the hamster skin,
with only DMBA consistently giving rise to melanotic tumors and, in addition, to numerous minute melanotic lesions; only MC was associated with a single small melanotic
tumor. Multiple melanotic lesions were observed in the MC-, 2-A and, to a lesser extent,
BP-treated hamsters. Some chemical specificity therefore determines this result. In
previous studies, the only melanotic tumors reported have been seen following treatment
with DMBA or 5, 9, 10-trimethyl-1, 2-benzanthracene [19, 26]. With regard to DMBA,
it was found that single applications of the carcinogen gave rise to melanotic tumors,
and repeated applications given weekly produced squamous cell tumors. Hence, a definite
relationship exists between dosage and response. Of the other carcinogens tested, only
MC and 2-A gave rise to squamous cell and adnexal tumors. Surprisingly, neither epidermal nor melanotic tumors were observed with BP.
Straile [220]: This paper refers to that of GHADIALLY AND BARKER [75], who reported
that clusters of pigmented cells are normal in the hamster and should not be considered as
nevi. They produced melanotic tumors with repeated applications of DMBA. In this
paper, attention is called to the tylotrich follicle of the hamster, which is the largest of the
pelage follicles and appears to be highly specialized for sensory function. There are two
distinct hypotheses that can partially explain the histogenesis of the carcinogen-induced
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melanotic tumors in the hamster: They may arise from dermal melanocytes of the tylotrich
follicle and invade and envelop the adjacent neural elements or, on the other hand, neural
components of this richly innervated hair follicle may undergo carcinogenesis directly.
Toth et al. [226]: Urethan in the drinking water (0.2 to 0.4%) was given to 5- to
7-week-old hamsters for a total of 42 weeks, spread over 48 weeks, with treatment omitted
between the 40th and 48th weeks. This gave rise to melanotic tumors of the skin, papillomas and carcinomas of the forestomach, adenomatous polyps of the cecum, pulmonary
adenomatosis, mammary tumors, hepatomas and hemangiosarcomas. Other tumors
occurring in the controls appeared to have been enhanced. After the fourth week, all the
survivors in the urethan-treated group developed one or more tumors.
Flank Organ
Aigard et al. [6]: This paper is not directly pertinent to carcinogenesis. It furnishes an
anatomical baseline and discusses the embryology of the flank organ.
Aigard [2]: Evidence derived from tissue-culture studies of an estrogen-induced
dependent neoplasm of the kidney and an androgen-estrogen-induced dependent tumor
of the flank organ in Syrian hamsters suggests that both are of epithelial origin. Cells
from these hormone-dependent tumors can be grown in hormone-free media; the addition
of crystalline hormone does not enhance growth or survival. However, when the kidney
tumor is cultured as an 'organ' fragment, growth does not occur, and survival time is
greatly reduced unless estrogen is present in the culture medium. Responses to doses
of 5, 10 and 25 ftg of diethylstilbestrol per ml of culture medium indicate a graded effect;
more mitoses occur at the higher value.
Aigard [3]: Organ cultures of the flank organ are hormone-dependent, whereas
tissue cultures are not. This parallels the behavior of the tumor in vivo.
Aigard et al. [7]: This is an enzymological study on the flank organ tumors which
arise with estrogen-androgen treatment. Initial samples were taken at intervals during the
life history of the neoplasm for isoenzyme histochemistry, using both microscopic methods
and acrylamide-gel electrophoresis. It appeared that LDH diminishes during the initiation
of stage-one nodules and that there is gradual and variable synthesis of the enzyme,
probably in more than one form, during the transformation of stage one to two masses.
Ultimately, there occurs marked elaboration of additional types and quantities of LDH
during the development and growth of the definitive stage-three tumor.
Kirkman [105]: This is a review which competently summarizes the information
available on estrogen-induced kidney tumors and on three types of tumors induced by
androgen-estrogen combinations, namely, uterine tumors, epididymal tumors and
flank organ tumors.
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This organ, referred to as pigmented costo-vertebral spot, scent
gland, and by other synonyms, is apparently resistant to locally applied
carcinogens, but will undergo malignant transformation when a
systemic hormonal imbalance is caused by the simultaneous administration of estrogens and androgens. Under these conditions, malignant chaetepitheliomas containing melanotic as well as amelanotic
cells are formed in from 60 to 200 days. These tumors are hormonedependent and will metastasize when transplanted into the cheek
pouches of estrogen-androgen-treated animals.
HOMBURGER
Kirkman [109]: This paper summarizes KIRKMAN'S views on the synergism of
testosterone in estrogen carcinogenesis (see also his later reviews).
Kirkman & Algard [111]: The morphogenesis and hormonal relationships of a unique
malignant basal-cell epithelioma in flank organs of the Syrian hamster are described. The
life history of this androgen-estrogen-induced tumor involves three stages: 1. the migration
of hair matrix cells into dermal sheaths and/or dermal papillae to form epithelial nodules
which become surrounded by connective tissue lamellae; these lamellated corpuscles
occur normally in males aged 185 or more days, but not in females; they require the presence of androgen and are inhibited by estrogen. S. Under the influence of exogenous
androgen they increase in size, up to approximately 1 mm in diameter, and the central
cores of epithelial cells migrate peripherally as radiating cords. 3. Under the influence
of exogenous androgen and estrogen together, the stage-two nodules increase in size and
fuse to form definitive stage-three neoplasms, the mean latent period for induction of
which is ca. 230 days, with a range of 110-500 days. Once formed, neither the spontaneous nor the induced tumors ever undergo complete regression, even with estrogen
treatment. With androgen treatment alone, stage-one nodules occur precociously, and
induced nodules appear in females and in gonadectomized or hypophysectomized hamsters. The effects of surgical interference and of other hormones upon the induction and
behavior of the tumor are described, as are its growth characteristics in both hormonefree and hormone-containing diffuse cell and organ cultures. The chaetepithelioma
metastasizes and is transplantable as a hormone-dependent tumor. Specific hormone
activity at the tissue level, rather than 'hormonal imbalance', is considered critical in the
induction and growth of this tumor. During 21 serial passages the transplanted tumor has
become autonomous. . .. Some semantic problems in oncology and possible modes of
hormone action in tumor induction and subsequent growth are discussed in relation to
this tumor.... The value of the neoplasm in studies of carcinogenesis is emphasized.
Kirkman et al. [113]: Since 1954 in has been found that early stages of androgen-estrogen-induced melanotic tumors in the Syrian hamster are associated with flank organ hair
follicles. Observations suggest that they arise probably from papillae and probably from
papillary rests. ... Three hundred seventy-five of these tumors have been observed
macroscopically, only in animals treated simultaneously with diethylstilbestrol and
testosterone propionate. In 36 variously treated and untreated animals microscopic
nodules occurred. It is believed that these are the nodules which arise from the hair
papillae and transform into tumors under suitable hormonal stimulation .... Melanotic
and amelanotic areas occur. Amelanotic areas frequently are DOPA-positive and will
blacken during incubation in tyrosin solution. Subcutaneous transplants and, in one case,
a lung, metastasis from a transplant, have been grown in vitro. Outgrowths from explants
include branching elements resembling dendritic cells; after both DOPA and Masson's
modified Bizzozero technics, the branching cells become darker than fibroblasts in the
same outgrowth. The branching cells are identified tentatively as melanoblasts, either of
neural crest origin or arising from macrophages .... The hair follicle tumors are histologically different from 6 melanomas encountered among 2,452 hamsters autopsied.
Kirkman etal. [122]: Benign tumors develop in the tela subcutanea under the pigmented
costovertebral spots of Syrian hamsters implanted subcutaneously with pellets of diethylstilbestrol and testosterone propionate. When the spots are excised prior to treatment
the tumors fail to develop. When the spots are transplanted to the abdomen, the tumors
develop there, but not at the original site. The tumors may be induced equally well in
either sex, intact or gonadectomized. Following removal of the pellets the tumors stop
growing, but show no regression. The shortest treatment period followed by grossly
visible tumors is 59 days; ordinarily, tumors are not expected within less than 150 or
200 days of treatment. Progesterone does not prevent tumor induction. After the tumor
has appeared, the spot may be removed without interfering with tumor growth, or a
tiny fragment may be transplanted subcutaneously, or to the cheek pouch, where it
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grows quite independently of pigment, but only in the presence of estrogen and androgen.
Hypophysectomy does not stop growth of the tumor or interfere with its successful
transplantation. Subcutaneous transplants metastasize regularly to the lungs. Somewhat
similar multiple tumors may be induced by testosterone propionate alone, but only
after a relatively long latent period; these androgen-induced tumors have never exceeded
a millimeter or two in diameter, however, even after 900 days of treatment.
There is a question whether the tumors described above are
benign or malignant. Note that subcutaneous transplants metastasize
to the lungs.
Oberman & Riviere [152]: DMBA, BP and MC were locally applied to the flank organ of
golden hamsters for forty days. Hyperplasia was a constant phenomenon in the epidermis,
which was more marked with DMBA, and the number of sebaceous glands in the flank
organ was reduced. This reduction, very marked with DMBA, is less pronounced with
BP and quite weak with Me. The pigment of the organ does not seem to participate in
these reactions.
See Siraile [220], p. 174.
Cheek Pouch
Dachi [38]: Nine-week-old hamsters were used. The carcinogen employed was
DMBA in mineral oil and Tween 60. Tween 60, when used with DMBA, showed a marked
decrease in the latent period for tumor induction, compared with control tumors induced
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The cheek pouch is well suited for sequential studies of the early
phases of carcinogenesis. Several studies of this type have been done,
and histological and electron microscopic as well as chemical observations have been reported. In most of these cases, DMBA or Me were
employed as carcinogens.
Use of the cheek pouch for comparative studies with skin carcinogenesis has been referred to above.
In the majority of studies, the cheek pouch epithelium was found
to be somewhat less susceptible to chemical carcinogenesis than the
epidermis and there is some evidence that fluorescent material penetrates more slowly into the cheek pouch surface than into the skin.
However, dosage and dose schedules also influenced the rate of
tumor formation.
Croton oil, Tweens and mechanical irritation are effective cocarcinogens in the cheek pouch, but age appears to be a modifying factor
of cocarcinogenesis. Prednisolone and methotrexate shortened the
time of latency of DMBA-induced cheek pouch tumors; vitamin A
deficiency also increased the rate of tumor formation. Tobacco smoke
condensates, snuff and betel quid have been applied to cheek pouches
with negative results. However, the studies using smoke condensates
were not intensive enough to be conclusive.
HOMBURGER
with DMBA alone. Results: 0.5% DMBA in mineral oil applied until appearance of tumors:
latent period, 46±5 days; with Tween, 45±3. This was when the carcinogen was applied
until tumor appearance, and there was no difference. However, when only 15 applications
were made and then the latent period was measured for the two groups, it appears that
with the carcinogen alone there was an average latency of 73 to 91 days, and with Tween,
45 to 47 days.
Dachi [37]: Studies were carried out on the role of polyoxyethylene sorbitan monostearate (Tween 60) as a promoting agent in DMBA-induced carcinogenesis of the hamster
cheek pouch. DMBA in concentrations of 5 and 2% was dissolved in Tween 60 and
applied to the cheek pouch for varying intervals. The effects were compared with those
produced by using a mineral-oil vehicle for the carcinogen. The reactions of skin and
pouch mucosa to Tween 60 were also compared. With 2% DMBA dissolved in Tween,
the latent period for tumor appearance was shortened by 2-3 weeks and decreased the
life-span of the tumor-bearing animals. In a 5% concentration it exhibited marked systemic toxicity. In this group, the latent period for tumor appearance was unchanged, but
the animals died shortly after the appearance of the initial tumors. Autopsy revealed
non-specific degenerative changes in the liver. In a group receiving 5% DMBA in Tween
60 in a dose which is subcarcinogenic with a mineral-oil vehicle, the toxic effects were
less marked, and a few malignant tumors were produced. Applications of Tween 60 to
skin resulted in a marked thickening of the prickle-cell layer and mild hyperkeratosis. No
such effects were obtained in the cheek pouch.
Delaru et al. [40]: Seventy-seven adult hamsters were used. Fifty-five were treated
by injection of DMBA dissolved in benzene and olive oil, 20 mg for a solution of 10 cc
of equal parts of olive oil and benzene. Twenty-two animals received implantation of pellets
of 90 mg paraffin with 10 mg DMBA. The injections were repeated 4 to 5 times during a
month. The pellets were left in situ after injection. The results showed that D MBA causes
a modification of blood vessels and tissues such as occurs in inflammation, but the phenomenon differs from inflammation produced by burns, cauterization, trauma and
sensitization reactions in that it is progressive rather than cyclic, and also in that there
is formation of a hyaline connective tissue resembling hyaline tissue in the stroma of
malignant tumors.
Dunham & Herrold [64]: This paper contains a table on the life-span and spontaneous
tumor incidence in the hamsters used by these authors. Life-span went up to 2.5 years,
and the percentage of tumors varied from 5.6 to 29.5. The carcinogens used on the cheek
pouch were DMBA and Me in pellets of beeswax, and they produced carcinomas. All
of the other compounds tested did not produce any tumors (betel quid, tobacco, tobacco
tar, black pepper, incense, nutmeg, etc.). The materials were left in place for periods
varying from 1 to 31 months.
Ghadia!!J& Illman [76]: This is a study to determine how far the tumors induced by
DMBA in hairy skin differ from those produced in a squamous cell epithelium without
hair follicles. For this purpose, the cheek pouch of male hamsters of about 30 g weight
was exteriorated and implanted into the skin, then painted with a 2% solution by weight
of DMBA in a mixture of equal parts of anhydrous lanoline and liquid paraffin once a
week for 29 weeks. Some animals were observed four weeks beyond that time. The
tumors which formed in the exteriorated cheek pouch, which in effect presented an area
of hair-free squamous epithelium, were papillomas, morphologically quite distinct from
the keratoacanthomas that arose from the surrounding hairy skin. This supports the idea
that most of the tumors arising from hairy skin during chemical carcinogenesis are of
hair-follicular origin.
Kendrick [101]: The effects of topical applications of DMBA and of cigarette smoke
condensate upon hamster cheek pouch mucosa were studied .... The neoplastic response
to DMBA varied with the solvent employed. Over a period of 34 weeks, benign and
histologically malignant tumors were induced in cheek pouch mucosa, but no metastases
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were present at the termination of the experiment. Some carcinogen-treated animals
developed epithelial tumors in the forestomach. Hemopoiesis was observed in the spleen
and liver of tumor-bearing animals .... Cigarette smoke condensate and its solvent each
elicited transient inflammation and persistent epithelial hyperplasia, as well as dysplasia,
in the muscosa of hamster cheek pouches. Croton oil exerted no detectable influence
upon the cheek pouch when administered either alone or in combination with cigarette
smoke condensate. No tumors were induced in cheek pouch mucosa with cigarette
smoke condensate applied at regular intervals for either a limited period of time or over
the life-span of the animals, and the question of preneoplastic change in areas of hyperplasia and dysplasia was not resolved.-The fluorescence of cigarette smoke condensate
was shown to penetrate the entire thickness of epidermis within one hour after topical
administration to hamster skin, and to penetrate the epithelium of hamster cheek pouch
muscosa within 2 hours after topical application. Fluorescence was neither abolished nor
reduced by immersion of sections of treated skin in chloroform for 24 hours.
Kreshover & Salley [124]: This is a review article which includes considerations on
many animals other than hamsters; however, with respect to hamsters, it is stated that
the intraoral palatal tissues of hamsters are unaffected by either daily exposures to whole
tobacco smoke or tri-weekly applications of BP, periods of observation being 16 and 6
months, respectively. Factors of sex, strain, vitamin B deficiency and desalivation have
no apparent influence on this tissue resistance. In contrast to the resistance manifested
by the hamster palate, the cheek pouch shows infection and edema after eight months
of tobacco application, and epidermoid carcinoma after four months of BP painting.
Increased gonadal hormone function in hamsters apparently does not influence the
pattern of BP-induced carcinogenesis in the cheek pouch.
Listgarten et al. [128]: Ultrastructural alterations occurring in hamster cheek pouch
epithelium as a result of DMBA applications revealed a marked disturbance in the intercellular relationship of epithelial cells. Widening of the intercellular spaces took place
as early as the second day of DMBA applications. Similar changes were observed when
a non-carcinogenic irritant (xylene) was applied. It is suggested that such changes may
facilitate the penetration of a carcinogen to the stratum germinativum and the underlying
connective tissue. The most striking feature observed in the cells obtained from tumor
tissue consisted of a peculiar clumping of tonofibrils on the periphery of the cytoplasm,
with a concomitant depletion of the tonofibrillar elements from the main portion of the
cytoplasm.
Meskin & Woo{{rey [135]: Historadioautographic localization of C14-labeled DMBA
was studied during the initial period of hamster cheek-pouch carcinogenesis. Immediately
following painting of labeled carcinogen there was rapid absorption through the intact
pouch epithelium. Surface and epithelial radioactivity decreased progressively throughout
the next 24 hours. Submucosal radioactivity tended to remain higher, and to decline
more slowly, than surface and epithelial radioactivity. Patches of submucosal radioactivity persisted beyond 24 hours after painting, but generally declined to the background
by 48 hours. Mononuclear inflammatory cells tended to localize at the site of increased
submucosal radioactivity after multiple paintings. The polymorphonuclear infiltration
which occurred after epithelial ulceration bore no relationship to radioactive foci.
Moore & Christopherson [142]: This study involved 30 male and 30 female randombred
albino hamsters, 3 to 6 months of age. The cheek pouch was exteriorized through incision
in the back of the animal and pulled entirely outside. A pedicle graft of pouch was made
to form a dry pouch of epithelium. Fifty-eight animals recovered from the procedure.
After two weeks, fibrosis beneath the epithelium caused some wrinkling of the pouch
surface. Group 1 (the control) received no treatment; Group 2 received cigarette smoke
condensate which was painted on the exteriorized pouch (40 mg of condensate per application); Group 3 received DMBA paintings with a camel hair brush on the pouch, three
times a week. No solvent was used. DMBA was used in an 0.5% solution in liquid petro-
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HOMBURGER
latum, 1 mg per application. The skin studies were done on 41 shaved hamsters, half
golden and half albino, which were painted from anterior back to tail. Group 4 received
paintings with cigarette smoke condensate. Group 5 received DMBA paintings. The
frequency and dosages were the same as for the pouches. After painting periods of up
to 683 days, histological examination revealed hyperkeratosis and slight hyperplasia in the
group treated with cigarette smoke condensate (Group 2). The skin showed no lesions.
After 90 days with DMBA there was invasive squamous cell carcinoma originating in the
skin, often with multiple foci. The pouch epithelium itself showed only hyperplasia.
There was a single carcinoma in situ in the pouch after 108 days. In the skin-treated animals, cigarette smoke condensate caused atrophy of the pilosebaceous apparatus. This
appeared in all animals after 300 days. There were no other changes up to 721 days. D MBA
skin treatment caused cancer in all animals by 100 days. After 3 to 4 paintings there was
already marked hyperplasia and parakeratosis, disappearance of sebaceous glands and
atrophy of the hair follicles. There were three melanotic tumors in the treated skin and
three melanotic tumors in the skin of the animals with the exteriorized pouches. Two
animals in the DMBA-treated group had carcinoma of the lips, apparently from licking
DMBA. It is interesting to note that the exterioration of the pouch and transformation
into a dry epithelial sac apparently reduces the susceptibility of this tissue to DMBA. It
must be noted that the condensate used in these studies produced only 3% skin cancer
in Swiss mice [143]. However, here too, no solvent was used with the condensate.
Moore & Miller [143]: Cigarette tar obtained from a smoking machine (average
temperature at height of combustion, 700 0 C producing 35 mg of tar per cigarette, 30 cc
smoke puffs, 1 puff per minute, was applied by cotton and gauze wads, 1 cm in diameter
(440 mg of pure tar without solvent) into the oral pouch of hamsters, where it was secured
by a thick suture. BALB/c mice were painted three times a week on the shaved back, 40 mg
per application; no solvent was used. Pouches were also palpated in hamsters 3 times a
week and some pure benzpyrene powder was placed into these pouches 3 times a week.
Of 80 hamsters treated with tar wads, 55 survived for more than a year; 40 were treated
longer than 18 months; 10 for more than 24 months; and one for 30 months. There were
no tumors. Thickening of the epithelium, chronic inflammatory reaction, etc. were observed. No tumors were found in BP-treated animals which lived for up to 23 months. In
the mice also, although 50 survived for more than a year and 20 for more than one year
and one year and a half, there were only one squamous cell carcinoma at 14 months and
a second one at 18 months. There was a long discussion concerning the negative result,
but the one important factor, namely, that no solvent was used, is not mentioned by the
authors. This may be the difference in this experiment that explains the negative results.
Mori ef al. [144]: Histochemical observations were made of hydrolytic enzymes and
dehydrogenases during experimental carcinogenesis induced by DMBA in the hamster
cheek pouch. Alkaline phosphatase activity was found on the surface of the
neoplastic epithelium with heavy inflammation and non-specific esterase, and p-glucuronidase had a moderate to high activity in the germinal layer of the neoplastic epithelium. Succinic dehydrogenase activity was shown in the germinal layer, but malic and lactic
dehydrogenase reacted more intensely than did succinic dehydrogenase. The hornified
layer of neoplasms was devoid of these three dehydrogenases. Acid phosphatase activity
was strikingly present. Aminopeptidase and polysaccharide in neoplasms showed little
or no reaction. In the stromal elements of the tumors there was little or no activity of
these enzymes.
Morris [145]: The purpose of this study was to investigate changes in oral mucosa
during neoplastic alteration. The hamster cheek pouch mucosa was studied in the normal
state, when undergoing premalignant hyperplasia, and after the production of squamouscell carcinomas, in response to repeated applications of DMBA. Bonin's fixed tissues were
stained for reticular fibers according to the method of Foot. The periodic acid-Schiff
(PAS) technique was employed with and without pretreatment with amylase, hyaluroni-
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dase and pyridine. Staining with toluidine blue was carried out both before and after
sulfation with and without pretreatment with hyaluronidase. Serially cut sections were
subjected to Hale's iron absorption staining procedure. The basement membrane was
well visualized in Foot-stained and PAS-treated tissues. The PAS staining was not altered
by previous treatment with amylase, hyaluronidase or pyridine. The basement membrane
exhibited metachromasia only after sulfation and this staining was not changed by hyaluronidase pretreatment. Hale's procedure did not selectively demonstrate the basement
membrane. The basement membrane of epithelium undergoing preneoplastic hyperplasia
exhibited increased thickness and staining intensity in PAS-treated tissues and those
stained with toluidine blue after sulfation. This change was not evident in tissues stained
for reticulum or those viewed in the phase contrast microscope. The basement membrane
of epithelium contained in papillomatous tumors was less defined, thinner, and stained
less intensely than that of normal or hyperplastic epithelium. In areas of cellular invasion,
no basement membrane could be demonstrated.
Morris [146]: The cheek pouches of old hamsters are more resistant to carcinogen
stimuli than those of young hamsters. No difference in the rate of carcinogenesis response
is seen between the ages of 3 and 9 weeks. Five weeks appears to be the ideal age for hamsters used for experimental oral carcinogenesis, from the standpoint of easy manipulation
and tumor production. The 18-month-old hamsters which were used showed a significantly greater length of time for tumor formation. DMBA (0.5%) was the optimal concentration for rapid tumor production; there was maximum tumor response with minimum latent period and no toxicity; 0.1 and 0.05% produced graded submaximal responses
in tumor production; 1.5% was extremely toxic and caused ulcerations. Frequency of
application: shorter latent period for tumor development in animals exposed three times
per week than in those exposed twice per week. A smaller total dose is required to produce
tumors in all animals when the carcinogen is applied twice each week than when given
three times weekly. Neither sex nor caging conditions (3 or 4 hamsters caged together)
caused any differences.
Morris et at. [147]: Cheek pouches from experimental and control hamsters were
excised for analysis at various times during the first week and thereafter each week of
carcinogen application (0.5% DMBA 3 times per week, applied with a camel hair brush)
until the 13th week, at which time large tumors were present in all remaining animals.
Histological study revealed progression from inflammation, hyperplasia and local premalignant hyperplasia to small tumors and then large squamous-cell carcinomas. The
sulfhydryl group concentration, determined by amperometric titration of acid-soluble
fractions of cell-free extracts of the whole pouches of males, showed a biphasic curve with
an increased SH at 36 hours, followed by a decrease at 60 hours. Pouches from the females
did not exhibit the early rise, and the decrease was more profound. The SH concentration
remained low until the period of tumor production and rose slowly in the whole pouches.
Tumor tissue contained 40% of the concentration of soluble SH found in the non-tumorbearing tissue from which it was removed (see also: Proc. amer. Ass. Cancer Res. 3: 144
[1960]).
Reiskin & Mendelsohn [167J: This is a kinetic analysis of the behavior of mitotic cell
division in tumors induced in albino hamsters by painting the cheek pouches with DMBA
and comparing these data with similar data obtained in unpainted pouches. Radioautographs were made after the administration of tritiated thymidine and various calculations
reveal a constant behavior of the rate of proliferation in the tumors, as opposed to that in
the nonmalignant tissue of origin.
Reiskin et at. [168]: A 0.5% mineral oil solution of DMBA was painted tri-weekly
onto the cheek pouch of young adult albino hamsters. This procedure produced grossly
observable tumors in all animals within 7 weeks. Pouches from three experimental and
one control animal were excised for analysis at various times during the first week and
thereafter each week of carcinogen application until the 13th week, at which time large
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The Syrian Golden Hamster in Chemical Carcinogenesis Research
HOMBURGER
tumors were present in all remaining animals. Histologic progression from normal through
inflammation, uniform hyperplasia, localized premalignant hyperplasia, to small and then
large squamous-cell carcinomas was observed. Soluble -SH was determined by amperometric titration. Results show a biphasic curve with an increase in -SH at 36 hours,
followed by a decrease at 60 hours which remained until the period of tumor production.
Tumor tissue contained about 40% of the concentration of soluble -SH exhibited by the
nontumor-bearing tissue from which it was removed. Values for the latter fell within the
range of control tissue.
Renstrup et al. [169]: Two series of experiments were arranged to investigate the effect
of mechanical irritation upon chemically induced carcinogenesis in the cheek pouch of the
golden Syrian hamster (Cricetus auratus). Fifty-four 3-month-old female animals divided
into 6 equal groups were used. An 0.5% concentration of DMBA in an adhesive vehicle
was applied to the check pouch 3 times per week to 3 groups of animals throughout the
experimental period, which extended from 4 to 24 weeks. In four groups, a twisted wire
ligated around the lower first molar and projecting into the cheek pouch served as a local
irritant. Gross and microscopic observations indicated the following: mechanical irritation
alone resulted in persistent ulceration; by the eighteenth week, carcinoma was observed
in all animals treated either with the carcinogen or with the carcinogen-mechanical
irritation combination. The first series was conducted to determine the tissue response to
the carcinogen, mechanical irritation and the vehicle. The second series of 140 animals
was confined to comparing chemically induced carcinogenesis with and without mechanical
irritation and showed that mechanical irritation accelerated tumor development.
Renstrup et al. [170]: A carcinogen, 0.5% DMBA in an adhesive vehicle (Drabase)
was painted onto the cheek pouch of hamsters with a brush 3 times per week, and chronic
irritation was produced by a steel wire mounted on the teeth. No tumors occurred with
chronic irritation alone, but chronic irritation enhanced the appearance of chemically
induced tumors. After 18 to 24 weeks there were 11 animals out of 11 with carcinoma in
the groups that had received both chronic irritation and carcinogen (the same result was
obtained with the carcinogen alone). However, the first tumors with carcinogen alone
appeared in 10 weeks, whereas the first tumors with both irritation and carcinogen
appeared already at 4 weeks.
Rowe& Gorlin [184]: This study indicates that in the carcinogen-treated cheek pouch
of the Syrian golden hamster, vitamin A deficiency promotes epithelial tumor production.
This was done on 60 male and 60 female golden hamsters at 25 days of age. At 45 days
of age, the animals were placed on an experimental vitamin A-deficient diet. The carcinogen
used was DMBA in liquid petrolatum solution, 0.5% by weight. Topical applications
were made to the buccal cheek pouch twice a week for 13 weeks. Animals were killed 20
weeks after the vitamin A-deficient diet was started. A control group received the vitamin
A-deficient diet plus vitamin A supplement. Vitamin A deficiency increased the rate of
tumor formation. It was also noted that a higher tumor incidence prevailed in the group
fed ad libitum than in the group with restricted caloric intake; this was in accordance with
TANNENBAUM'S previous findings that tumor production is inhibited by diet with restricted
caloric intake. However, this effect appears to be more than offset if the diet is deficient in
vitamin A.
Sabes et al. [187]: Sixty-seven golden Syrian male hamsters, approximately 40 days
old, were divided into four groups of 20,20, 19 and 7. The animals in Group 1 were
treated by painting the left cheek pouch with pure Tween 80 (polyoxyethylene sorbitan
mono-oleate). After drying for 1 minute, the previously painted area was swabbed with
2 drops of 0.5% DMBA in liquid petrolatum. The animals of Group 2 were similarly
treated by swabbing the left buccal pouch with 0.025% prednisolone acetate (Sterane)
followed by the application of the carcinogen. Group 3 was painted with Tween 80 alone.
No control group for liquid petrolatum was employed, since its noncarcinogenic properties
have been repeatedly established in the author's laboratory. The paintings were repeated
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every third day for a total of 27 applications over a period of 80 days. The latent period
in Group 2 (Sterane-treated) animals was 42 days, compared with Groups 1 and 3 in
which it was 60 and 63 days, respectively. Furthermore, at any stated time interval, the
tumor incidence was higher in the former group of animals than in the latter group. This
difference was statistically significant between 60 and 81 days. Microscopically, the incidence of invasive squamous-cell carcinoma was found to be higher in the Sterane-treated
group than in the Tween 80-treated group (P = < 0.02) at the end of the experiment. No
such difference was noted in the Sterane-treated and the carcinogen-treated groups.
Salley [195]: This is a review paper dealing with the question of whether sebaceous
glands and skin appendages are really necessary for chemical carcinogenesis, as has been
claimed by many papers. In the hamster cheek pouch, there is a stratified squamous
epithelium, such as oral mucous membrane, which contains no portals of entry, such as
mucous glands, or other accessory epithelial structures. There are only two minor salivary
glands described by GILLETTE in the medial and lateral aspects, respectively, of the
pouch. It is very rare for carcinomas induced by chemicals to arise in the area of these
glands. Excessive production of squamous-cell carcinoma in the hamster cheek pouch
has been achieved with tri-weekly topical applications of 0.5% DMBA, BP and MC
Latent periods range from 7 weeks with DMBA to 25 weeks with MC Tumors of the
intraoral mucosa proper as well as ear epidermis in the hamster have also been induced
by topical application ofDMBA and BP. The conclusion of this paper is that the epithelial
adnexae acting as requisites to chemical induction of tumors should be re-evaluated and
that probably they are not necessary.
Salley [194]: This is a histological study of changes occurring after the application
of carcinogen to the hamster cheek pouch; there are four distinct histological phases:
1. inflammation, 2. degeneration, 3. regeneration, and 4. hyperplasia.
Salley [196]: PD albino hamsters were used, and it was demonstrated that DMBA
or BP shows detectable fluorescence in hamster skin after one painting and in the oral
mucosa after three to four applications.
Salley [197]: Daily applications of smoke to the ears and lips of mice for up to 80
days showed only diskeratotic changes; Vitamin B deficiency enhanced this. In 20 to 24
months of daily smoking, no neoplastic changes were observed. When smoke was applied
to the oral mucosa of hamsters first treated with a small dose of carcinogen, squamous-cell
carcinoma resulted in 56% of the animals, as compared to 24% in those having only the
initiating carcinogen. In the oral epithelium of hamsters, smoke is cancer-promoting,
presumably by chronic irritation.
Salley & Kreshover [199]: This is a study of the hexokinase, glucose-6-phosphate
dehydrogenase and phosphogluconate dehydrogenase in extracts prepared from hamster
cheek pouches which were being painted 3 times weekly with DMBA; the animals were
studied when there was no change (approximately one week), and when there was
inflammation (second and third weeks), when there was hyperplasia after the third week,
in the preneoplastic hyperplastic phase, and with papillomas after about 7 weeks, and
finally, after the appearance of malignant tumors. It was concluded that changes of
phosphogluconate show the greatest degree of correlation with the neoplastic state, as
compared with the hyperplastic state.
Scott et al. [202]: A 0.5% mineral oil solution ofDMBA was painted tri-weekly onto
the cheek pouches of hamsters. Gross tumors appeared in all animals within 7 weeks.
The pouches were excised at intervals during the first week and weekly thereafter for
13 weeks. Enzyme activities were determined on extracts of whole pouches or tumors and
tissue from which tumors had been removed. After minor fluctuations of all three enzymes
during the inflammatory reaction and quiescent period, hexokinase (Hex.) and phosphogluconate dehydrogenase (PGD) fell to 50% and 40% of control after 2 weeks, slowly
rising toward control values during the period of hyperplasia and tumor formation. In
tumors, the Hex. was 1.5 to 5.5 times, and PGD 2 to 7 times the control. In the residual
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pouch tissue, both enzyme levels ranged from normal to 3.5 times. The glucose-6-phosphate dehydrogenase increased continuously from 4 or 5 weeks, and activities were 2 to 5
times the control in both tumors and surrounding tissue.
Scott et al. [203]: This is a study of the hexokinase, glucose-6-phosphate dehydrogenase and phosphogluconate dehydrogenase in extracts prepared from hamster cheek
pouches which were being painted 3 times weekly with 9,10-dimethyl-1,2-benzanthracene;
they were studied when there was no change (approximately 1 week), when there was
inflammation (2nd and 3rd week), when there was hyperplasia (after the third week), in
the preneoplastic hyperplasia phase, with papillomas (after about 7 weeks) and finally,
after the appearance of malignant tumors. It was concluded that changes of phosphogluconate show the greatest degree of correlation with the neoplastic state as compared
with the hyperplastic state.
Shklaret al. [208]: Forty-eight 6-month-old male and female Syrian hamsters were studied for the effects of systemically injected methotrexate upon the process of chemical carcinogenesis of the buccal pouch. Twelve animals had their right buccal pouch painted
three times weekly with an 0.5% solution ofDMBA in heavy mineral oil. Twelve animals
were painted with DMBA and also were injected subcutaneously 3 times weekly with
0.0625 mg of sodium methotrexate. The remaining animals were controls. In the animals
given methotrexate injections, chemically induced carcinomas of the buccal pouch
appeared more rapidly than in the DMBA controls. The tumors were also more anaplastic
and of greater size. The DMBA- and methotrexate-induced tumors, 10-15 mm in diameter,
appeared after about 12 weeks. With DMBA alone, there were no tumors after 8 weeks
and only small localized tumors after 12 weeks. With methotraxate alone, there were no
changes.
Silberman & Shklar [213]: Hamsters aged 2 to 3 months react differently to the application to the cheek pouch of DMBA and croton oil or of these substances alone than did
hamsters aged 12 to 14 months. In the young animals, the application of 1% croton oil
retarded the appearance of cancer induced by 0.5% DMBA, whereas in the older Syrian
hamsters, the application to the buccal pouch of 0.5% DMBA and 1% croton oil resulted
in an enhancement of carcinogenesis when compared to the application of 0.5% DMBA
alone. In some of Shubik's experiments, croton oil was not cocarcinogenic in the skin of
hamsters.
Tabah et al. [221]: The carcinogenic effects of tobacco tars on the mouse skin have
been reported by several investigators. In this experiment, it was attempted to obtain data
on the carcinogenic properties of tobacco tars in relation to a mucous membrane, as
compared with a well-known carcinogen. '" Saturated solutions of tobacco tars or
solutions of DMBA were applied 3 times weekly to the cheek pouch mucosa of hamsters,
for a period of 12 months. A saturated solution was prepared in chloroform, which was
allowed to evaporate before the application. In a control group of animals, corn oil alone
was used .... In the group of hamsters in which saturated solution of tobacco tars was
used, 23% of the animals showed nodules and thickening of the distal end of the pouch
after 4-8 months of application. In some of these animals the nodules resolved spontaneously after 2-3 weeks; others persisted until the animals were sacrificed. Histological
sections of pouches bearing palpable nodules showed marked fibroblastic proliferation
beneath the epithelial surface layer, which was frequently ulcerated. The newly formed
collagenous tissue extended for a considerable distance into the submucosa and in many
places replaced muscle or salivary gland. The picture was that of marked and slightly
atypical fibroplasia. - In the DMBA group, tumors were observed to develop in 10%
of the hamsters. The tumors appeared to arise from the squamous epithelium of the cheek
pouch mucosa and were classified as squamous-cell papillomas and carcinomas.
The Syrian Golden Hamster in Chemical Carcinogenesis Research
185
Oral Cavity
See Dacbi [38], p. 177.
Dachi & Laney [39]: This is a study of dental appliances which were fixed to the
hamster palate. The conclusion is drawn that absence of tissue changes for nine months
suggests that self-cured acrylic resin possesses no carcinogenic properties for the hamster
mucosa.
Salley [196]: PD albino hamsters were used in this study. It was demonstrated that
DMBA and BP show detectable fluorescence in hamster skin after one painting, and in
the oral mucosa after 3 to 4 applications.
Salley & Kresbover [200] : Carcinogenic hydrocarbons, D MBA and BP, were respectively applied to the palatal mucosa, cheek pouch and ears of two groups of 40 hamsters
each. Malignant neoplasia was elicited in 54, 100 and 100% of the respective tissues of
survivors when the former compound was used, and in 16, 94 and 100% with the latter,
indicating susceptibility of the intraoral mucosa to chemical carcinogenesis of a lesser
degree than susceptibility of cheek pouch and skin of ears.
See Salley & Kreshover [199], p. 183.
Stahl [216] : One hundred twenty hamsters obtained from Albino Farms, Redbank, New
Jersey, genetics undetermined, weighing an average of 36 g at the beginning of the
experiment, received applications of an 0.5% solution of DMBA in mineral oil. This was
painted three times weekly on the medial wall of the left cheek pouch of each hamster,
as outlined by MORRIS; the experimental period lasted for 124 days, during which time
51 hamsters were lost prior to sacrifice. The animals were killed in groups of 2 on the
second and sixth days of each week of the experiment; immediately prior to sacrifice, a
smear of the experimental site was taken and stained by the Papanicolaou method. The
observations show that carcinogenesis proceeded from initial irritation and inflammation
to intraepithelial atypia and papillomatous growth and, finally, frank malignancy, and
that these stages were reflected in the cytological study as well as in the histological
specimen.
S tabl [217]: Sixty-nine male hamsters weighing 36 g at the beginning of the experiment
were treated with an 0.5% solution ofDMBA in mineral oil 3 times weekly in the medial
wall of the left cheek pouch. This produced invasive carcinoma in about 2 months. Ten
untreated hamsters were used as controls. Observations on the periodontal tissue of the
tumor-bearing animals are reported; they do not show specific lesions.
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The epithelium of the oral cavity (as that of the cheek pouch)
is also less susceptible to chemical carcinogens than the skin. Topically applied carcinogens were found to penetrate into the skin after
one painting, but penetrated into the palatal epithelium only after
3 or 4 paintings. Susceptibility to carcinogens was increased by
vitamin B deficiency.
The daily application of cigarette smoke for two years failed to
produce any tumors. However, daily smoking increased the tumor
yield produced by small doses of DMBA from 24 % to 56 %, thus
suggesting that smoke was cocarcinogenic. The palatal mucosa of
hamsters has also been used to study early phases of carcinogenesis
by cytology and to establish the absence of carcinogenic effects of
self-cured acrylic resins.
186
HOMBURGER
Sallry et al. [198]: Evidence was obtained that chronic thiamine deficiency decreases
the time of latency of chemically induced oral cancer. The animals used were the PD
strain albino hamsters. The carcinogen used was 0.05% DMBA in acetone.
Peacock et al. [154a] : No neoplasms were found in 124 golden hamsters who received
surgical implants of snuff, tobacco and chewing gum in their oral pouches. The implants
remained for the major portion of the hamster's life.
While the respiratory tract of the hamster is resistant to respiratory
ailments which are common in other rodents, the tracheobronchial
tree is susceptible to chemical carcinogens that are introduced through
the trachea in a variety of ways. Since spontaneous bronchiogenic and
pulmonary cancers are extremely rare, the Syrian hamster lends itself
well to study of chemical carcinogenesis in the respiratory tract. In the
hamster, however, as in other rodents, the respiratory tract appears
to be far less sensitive to topical carcinogen application than the skin.
Oily solutions, aqueous suspensions and aerosols have been
introduced into the respiratory tract and DMBA and BP have produced neoplastic changes. Minimal effective doses of these carcinogens
can be calculated and Tweens have been found to promote carcinogenesis by BP. Tobacco smoke condensates were neither carcinogenic
nor cocarcinogenic in this system, although metaplastic changes and
papillary noninvasive tumors were produced. Direct smoke inhalation
only led to metaplasia and papillary proliferation.
Adsorption of BP and DMBA onto metal particles increased the
carcinogenicity of hydrocarbons, whereas some of these metal dusts
alone were merely irritant.
Diethylnitrosamine (DENA) given either by tracheal installation
or by ingestion caused squamous-cell papillomas of the trachea and
bronchi. In animals receiving dimethylnitrosamine (DMNA), various
types of liver cancer and a renal adenoma were also observed. In
rats the liver is the most susceptible organ to nitrosamine carcinogenesis, whereas in the hamster the epithelium of the tracheobronchial
tree and of the anterior and posterior nasal cavities respond most
strikingly to this type of chemical carcinogen. The study of nitrosamine
carcinogenesis is of practical importance because nitrosamines are
thought to occur in tobacco smoke.
Studies of metabolites of DENA and DMNA as well as injection of
nitrosamines into pregnant animals with ensuing bronchial cancer
in the offspring suggest that carcinogenic metabolites of the nitro-
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1?esjDirato~ ~ract
The Syrian Golden Hamster in Chemical Carcinogenesis Research
187
Argus & Hoch-Ligeti [9]: While this study does not deal with hamsters, it provides
information on the carcinogenic effect of nitrosamine derivatives in the rat. DMNA produced tumors with a variety of histological characteristics in the liver, lung and kidney.
Primary malignant tumors arose in one, two or all three of these organs in the same rat.
In the lung, squamous-cell carcinomas were found either as the only pulmonary tumor
or in association with bronchiolar or alveolar adenocarcinoma. DENA induced hepatocellular carcinoma in all rats, with metastases to the lung in many instances. One primary
kidney tumor was found. This is in contrast to the extreme sensitivity to carcinogenic
effects of nitrosamine of the hamster trachea and bronchi and the correspondingly much
lower sensitivity of the hamster liver to nitrosamine carcinogenesis.
Della Porta et al. [42]: This is a study on the injection through the tracheal tube of
colloidal suspensions of DMBA and tobacco tar directly into the trachea of hamsters.
The dosage of carcinogen in the individual treatments appears to be an important factor
in the effectiveness of the method. Forty-five repeated doses of SOy of D MBA yielded only
borderline carcinogenic action, whereas seventeen doses of 100y induced a significant
number of tumors of the tracheal-bronchial epithelium. On the other hand, tobacco tar
alone produced no malignant transformation, nor was there any evidence of a cocarcinogenic effect of the tobacco tar.
Dontenwill & Mohr [52]: Ten-week-old male hamsters, some castrated, were given
twice a week, 0.4 cc of an aqueous DENA solution, 1 cc in 250 cc of water by stomach tube.
The controls received saturated India ink solution by stomach tube to see how much
would reflux into the trachea. In the course of gavage of India ink, the ink was found in
the alveoli as well as in the bronchial-tracheal tree. These authors noted that addition to
the drinking water of DENA was impossible. In 21 animals treated with DENA, there
was diffuse papillomatous epidermoid metaplasia of the tracheal-bronchial epithelium
after from 4 to 19 weeks. Besides these changes there were tracheal or pulmonary tumors
in 37 animals. The first tumor was seen after 7 weeks. The others were noted 2 to 5 and
a half months later. There were also dystrophic liver changes. In contrast to the rats
there were, however, no liver tumors after 5 months. This is also in contrast to the work of
TOMATIS AND SHUBIK, who used DMNA and observed many liver tumors in hamsters.
With DMNA, no respiratory tract tumors were found. Since most animals live no longer
than five months after they have DENA-induced tracheal or lung tumors, it is impossible
to say whether the material (DENA) is really not carcinogenic for the liver.
Dontenwill & Mohr [57] : Twenty-one hamsters were treated from 2 to 6 months with
N-nitrosopiperidine 3 times weekly, subcutaneously,S cc in an aqueous solution, 1 :250.
This led to large proliferating papillomata of the trachea in animals treated for more than
two months. There was epithelial metaplasia in the trachea and bronchi and, in two
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samines may reach the respiratory epithelium via the circulation, and
indicate that for the pathogenesis of respiratory cancer, portals of
entry for the carcinogens other than inhalation may play a role.
However, both the respiratory and the parenteral routes may be
involved as in the inhalation experiments of WYNDER, which showed
that smoke inhalation following subcutaneous injection of DENA
promoted bronchial papilloma formation.
Hamsters have been used only rarely in the study of respiratory
carcinogenesis by asbestos. Cocarcinogenic effects of the chrysotile
form of asbestos have been noted, but neither this form nor amosite
had any carcinogenic effect when administered intratracheally to hamsters, while intrapleural injections produced malignant mesotheliomas.
HOMBURGER
animals, epidermoid cancer of the lung. There were no changes in the liver. In animals
treated with s.c. N-nitrosomorpholin twice weekly, 0.5 cc of 1 :125 solution in water,
there were tracheal and bronchial papillomas of the same type, and in animals treated for
more than two months, there was metaplasia in the liver. With the aqueous solution of
DENA 1 :250 in rats, an entirely different picture was seen, with inflammatory changes
in the lung and pseudoadenomatous proliferations, but no tumors. However, in 8 of 17
of these rats, there were hepatic carcinomas. In hamsters, all nitrosamine compounds
tested have a diffuse effect in the respiratory system. This may be due to a special disposition of the hamster lung. The carcinogenic effect in the lung appears to be a function of,
and the summation of, the single doses. The localization of the tumors is determined not
only by the mode of application and dosage, but also by the predisposition of the organ.
See Dontenwill & Mohr [54], p. 168.
Dontenwill & Mohr [55]: These authors stressed the usefulness of the hamster for
such studies (on the action of tobacco smoke condensates and cigarette smoke on lungs
of golden hamsters) because of the extremely low incidence of spontaneous carcinoma
and the rarity of pneumonia. Spontaneous tumors, in their experience, were less than two
in 1,000. All malignant tumors of the lung found in their hamsters were metastases from
other sites. Methods: Forty-two-day-old male hamsters were given, 3 times weekly, a
spray of cigarette condensate in sesame oil into the oral cavity or the tracheal-bronchial
tree; 0.07 g of the condensate, given each week, contained per 100 mg, 0.11' BP. Of the
37 animals used, only 6 died before the end of a year. The second experiment involved
smoking cigarettes in the usual manner into a chamber, exposing 10 animals daily for
147 minutes, smoking 10 cigarettes. Of 12 animals, 10 lived more than 6 months and
6 survived for 12 months. After 12 months it was found that the tracheal spraying of
condensate yielded 7 papillary, non-infiltrating tracheal tumors and many metaplastic
changes in the trachea and lung. In the inhalation studies of smoke there was only benign
metaplasia with focal papillary proliferation in the bronchi. Discussion of the method of
the smoking chamber concludes that this is probably not an effective method of smoke
exposure.
Dontenwill & Mohr [57]: This paper is a preliminary note on the special organ sensitivity of trachea, bronchi and lung in the hamster toward nitrosamine and certain nitrosamine derivatives. In contrast to the rat, where the same doses and routes of administration of nitrosamine produce merely inflammatory lesions in lung and trachea but a large
proportion of liver carcinoma, it is found in hamsters, regardless of concentration or
route of administration, that there are invariably epithelial metaplasia and carcinomas of
trachea, bronchi and lung. The papillary adenomas of the trachea are especially striking
and lead to death by suffocation. The author concludes that Syrian golden hamsters have
a special organ sensitivity toward nitrosamine not shared by the rat. (For details, see p.187.)
Dontenwill & Mohr [59]: This is a comparison, in 30 male castrated rats and 30 male
castrated hamsters, of the effect of AAF given for 6 months in the food in doses of about
5 mg per day. In the animals receiving treatment for more than 6 months, the hamsters
showed only one adenocarcinoma of the lung. This finding, also noted in the controls,
was described earlier by DELLA PORTA as an occasional spontaneous tumor. In the rats,
however, there were 43% small epidermoid carcinomas of the lung and no adenocarcinomas. In the subcutaneously treated animals, there was a difference in the species susceptibility of the lung to the effect of the acetaminofluorine. This is the opposite of observations made with DENA, where there occurred a high incidence of lung tumors in the
hamster and none in the rat.
Dontenwill & Mohr [49]: Hamsters were given, by stomach tube, 1 cc of DENA in
250 cc of water, of which they received 0.4 cc twice a week. The 34 animals that survived
4 and a half months or more showed cirrhotic changes in the liver, but no definite liver
carcinomas. Only five animals had no changes in their tracheal-bronchial tree. In all
others, there were multiple metaplasias of the respiratory epithelium, and in ten animals
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treated from 2 to 4Yz months, there were carcinomas of the trachea and bronchi. These
were papillomatous and partly keratinized epidermoid carcinomas. In some animals there
were multiple small bronchial carcinomas with infiltration into the lung tissue. The
possibility exists that there is regurgitation of the nitrosamine given by stomach tube.
The results obtained with DENA in this study differ from those obtained by others
with DMNA [225].
Dontenwill & Wiebecke [61]: This study was focused on the histogenesis of the tumors
which arise in the respiratory tract of Syrian hamsters after the administration of DENA.
In the bronchial epithelium there are metaplastic and proliferative changes of the epithelium as well as epithelial carcinomas, whereas in the trachea there is usually only a local
and rarely diffuse papillary proliferation of the mucosa. In order to clarify the mechanism
of these tissue-specific differences, hamsters received DENA subcutaneously, by rectum,
or by gavage, in 2 to 3 doses of 0.4 ml of a solution of DENA in water, 1: 250. Some
animals lived as long as 324 days. The animals also received tritiated thymidine and were
killed forty minutes after the injection of thymidine. Counts were made of the thymidine
in the proliferating or metaplastic cells in order to measure the synthesis of DNA. It was
found that the accelerated synthesis of DNA occurs in sites of metaplastic changes, but
does not further increase with infiltrative growth, and the organotropic factors of DENA
appear to be unrelated to the rate of proliferation of individual tissues. Most of the carcinomas appeared in regions of normally low proliferation rates, that is, in the small and
medium-sized bronchi. In the papillary hyperplasia of the trachea, the number of DNAsynthesizing cells is reduced sharply after carcinogen treatment is discontinued.
Druckrey & Preussmann [63]: Dialkynitrosamines form easily in high yield during the
course of the interaction of nitrous gases or nitric acid and secondary amines; under
dealkylizing nitrosation they also form from tertiary amines. The corresponding alkyl-acylnitrosamide also forms from alkylamides. Whenever such conditions exist, one must
anticipate the formation of carcinogenic nitrosamines; hence, this is a distinct possibility
in tobacco smoke. The carcinogenicity of tobacco smoke has never been fully explained
by the amounts of BP and other polycyclic hydrocarbons that have been demonstrated.
It is also a fact that nitrosamine-induced cancers correspond to those often found in the
human oral cavity, esophagus, urinary bladder, and lung. There are a number of secondary
amines such as diethylamine, pyrrolidine, piperidine and nor-alkyloids such as nor-nicotine
and anabasine and tertiary amines and alkyloids which have been demonstrated in tobacco
smoke. Nitrous gases have also been demonstrated in tobacco smoke. It is quite likely
that nitrosamines form during tobacco combustion, a fact which is made even more likely
by the known high nitrate content of tobacco (as high as 2% in some kinds of tobacco),
whereas in the ashes after combustion no nitrates are found. On the other hand, since
there are no appropriately significant methods for the demonstration of small concentrations of nitrosamines in complex mixtures, such as tobacco smoke nitrosamine, it has
actually not been shown chemically to exist in tobacco smoke. This requires further
investigation.
Herrold [83]: Previous experiments demonstrated that tumors of the trachea, bronchi,
anterior and posterior regions of the nasal cavity and liver are induced in Syrian hamsters
with DENA, administered either by intratracheal, intragastric or subcutaneous routes.
The purpose of this experiment was to determine what effect other routes of administration, including intraperitoneal, intradermal, and skin painting, have on the carcinogenic
action of DENA. The present study includes observations on three experimental groups
of Syrian hamsters to which DENA was administered for periods of 4-7 months. Fewer
hepatocellular carcinomas were induced by these routes, as compared with the results of
subcutaneous administration. The carcinogenic effect, by all three routes evaluated in the
present study, was greatest on the trachea, bronchi and nasal cavity, thus suggesting that
the major pathway of excretion for this carcinogen (DENA) or its metabolites is via the
respiratory routes.
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The Syrian Golden Hamster in Chemical Carcinogenesis Research
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Herrold [82]: The routes of administration in groups of animals varying from 3 to 19
weeks were intraperitoneal, intradermal and subcutaneous (in pregnant females only).
The results in the author's summary show that tumors of trachea, bronchi, anterior and
posterior nasal cavity and liver are induced in Syrian hamsters by DENA, irrespective of
route of administration. Epithelial atypism and proliferative lesions are observed in both
the liver and the kidney. With multiple and also single doses of DENA, the tumors
developed earliest in the trachea, bronchi and nasal cavity. These findings suggest that
the site of tumor formation may be determined by the metabolic pathway of this carcinogen. Excretion could occur via the liver, kidney and lungs, and the major pathways
may be by way of the respiratory system. (The groups of pregnant animals were too small
to demonstrate transfer through the placental barrier [see also 140]).
Herrold [85]: Three experimental groups, each containing twenty weanling Syrian
hamsters, were given DENA in 0.85% solution of distilled water for intradermal and
topical application, and in sodium chloride for intraperitoneal injection: Group 1, intraperitoneally 2 mg once a week for 4 to 7 months; Group 2, intradermally 3.5 mg once a
week for 5 to 6 months; Group 3, topically, undiluted, to the shaved interscapular region
with Camel Hair brush for 5 weeks, and then untreated for 2 months followed by treatment,
diluted 1:1 with distilled water twice a month for 3 months. Surviving animals: 15 in
Group 1, 19 in Group 2 and 8 in Group 3. In Group 1 the animals survived 7 to 14 months;
Group 2, 5 and a half months to 13 months; Group 3, 6 to 12 months. The average age
for all animals was 10 months. There were 15 epithelial papillomas of the nasal cavity
in 5 of the animals in Group 1, 10 in Group 2 and 6 in Group 3. Other tumors also occurred
and were described by the same author [84, 89]. These included olfactory neuroepithelial
tumors. The interesting point here is that the observed epithelial papillomas were induced
by DENA administered intradermally and topically to skin. Other carcinogens, such as
aflatoxin, 2,7-fluorenylenebisacetamide (literature reviewed) have also been known to induce various types of tumors of the nasal cavity, nasal lacrimal ducts and adjacent structures. This report stresses DENA as a carcinogen producing different types of tumors
and in this case producing epithelial papillomas of the nasal cavity by three different routes.
Herrold [84]: In the introduction, this paper notes that the first observation on the
toxicity of DENA was made in two men using it as a solvent and developing cirrhosis of
the liver [18]. This paper also contains the literature on the carcinogenicity of nitrosamine.
Twenty male and female Syrian hamsters received DENA in distilled water, 10 mg/ml,
starting at 1 to 2 months of age, 2 mg subcutaneously twice a week for 4 to 6 months.
Fourteen of fifteen surviving animals developed tumors of the nasal cavity. There was
higher frequency after subcutaneous administration than after administration by intragastric or intratracheal routes. Average age at death was seven months, caused byobstruction of the trachea and bronchi by multiple papillomas. The discussion contains
information on the comparative anatomy of the nasal region in the hamster and man. It
appears that the tumors which were observed in the hamster arise from olfactory
epithelium and hence are analogous to those described in man. As in man, they are locally
invasive. While in man they may metastasize, no metastases were observed in the hamster.
In this study it is demonstrated that either the carcinogen or its metabolite was transported in the blood stream and selectively deposited in the nasal epithelium, where it
caused cancers.
Herrold [81]: These experiments consisted in the comparison of effects of BP in
Tween 60, BP in distilled water, BP in olive oil, cigarette smoke condensate in Tween 60
and atmospheric pollutants in Tween 60. At the time of death, the hamsters treated by
intratracheal instillation were 6 to 12 months old. The only papillomas and carcinomas
found were in the group receiving BP with Tween 60. BP in distilled water caused only
some regenerative and atypical changes. BP in olive oil caused no changes. Cigarette
smoke condensate in Tween 60 caused some regenerative changes; atmospheric pollutants
in Tween 60 also caused some regenerative changes.
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Herrold & Dunham [88]: Previous experiments demonstrated that tumors of the
respiratory system, nasal cavity and liver could be induced in Syrian hamsters with DENA,
administered either by intragastric or intratracheal instillation. Substances administered
by these routes may reflux into the trachea or into the nasal passages. The possibility
cannot be excluded that DENA exerts a local action by both routes of administration.
This experiment was designed to test the effects of the subcutaneous administration of
DENA and to determine whether tumors of the respiratory system would result. DENA
was injected into Syrian hamsters twice a week for periods of 3 to 6 months. This study
includes observations on 15 hamsters that survived 4 or more months.-Tumors induced
were squamous-cell papillomas of the trachea, bronchi and bronchioles, tumors of the
nasal cavity and hepatocellular carcinomas. Induction of tumors of the tracheobronchial
tree and of the nasal cavity by the subcutaneous administration of DENA suggests that
the action of this carcinogen is not necessarily a local one. The inhalation route has been
stressed as the principal portal of entry for substances that are believed to induce bronchogenic carcinoma in man. The results of the present experiment suggest that carcinogens
or their metabolites may be transported by way of the blood stream and selectively deposited in the lung, or may be excreted by the respiratory system.
Herrold & Dunham [87]: BP was administered as a suspension in an aqueous solution
of polyoxyethylene sorbitan monostearate, Tween 60, or as a solution in olive oil. Repeated
intratracheal instillation of BP in Tween 60 induced papillomas and carcinomas of the
trachea, main bronchi and bronchioles and also a variety of atypical epithelial alterations.
The hamsters which died during the first few months had no tumors. Only 15 hamsters
surviving 9 months or longer are included in the analysis. With BP in olive oil, there
were 2 survivors of more than 9 months and no tumors.
Herrold & Dunham [89]: Intragastric and intratracheal instillation of DENA induced
multiple squamous cell papillomas of the trachea and bronchi and carcinomas of the
ethmoid region of the nasal cavity. Feeding DENA also induced carcinomas of the
liver and proliferative kidney lesions. The possibility that carcinogenic substances may
reach the human lung by pathways other than the respiratory tract is discussed.
See Levy [127], p. 170.
Miller et al. [138]: This paper does not deal with the carcinogenicity of asbestos per se
but, rather, explores the cocarcinogenic effect of two varieties of asbestos, chrysotile and
amosite. Golden hamsters from the Lakeview Hamster Colony were used when two
months old and received BP in 0.5% suspensions in aqueous Tween 60, with and without
the asbestos being added to the suspension. Intratracheal injections were then done under
anesthesia, and the animals were examined when they died or when they were sacrificed.
Conclusions: The conclusions were that the addition of the chrysotile type of asbestos to
BP injected into the trachea promotes carcinogenesis in the respiratory tract. The addition
of the amosite variety of asbestos to BP did not increase the tumor yield.
Mohr & Althoff [140]: This is a preliminary paper on subcutaneous injections of
2 to 14 mg of DENA, 2 mg daily, given to pregnant animals in the second half of their
pregnancy. Eight to 16 weeks after delivery the young were killed and the trachea, lungs
and liver were histologically examined. Metaplasia and papillomas occurred in the tracheal
area. There were also degenerative liver changes. Of 45 animals studied, 13 had metaplasia
of the trachea and 5 had papillomas of the trachea. In 14 animals there were changes in
the lungs. The extent of the liver lesions has not been studied and the question of the
dose-effect relationship has not been analyzed. Also, it is not yet known whether this
transmission of the carcinogen occurs through the placenta or through milk, since the
animals have not been foster nursed. Chemical studies on diethylnitrosamine in the
placenta, amniotic fluid and fetuses are also being planned.
SajJiotti et al. [190]: Prolonged grinding together of a fine crystalline dust of BP and
an inert heavier dust such as hematite (iron oxide) results in a mixture where the BP is
attached to the hematite. It is then suspended in saline and injected intratracheally into
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The Syrian Golden Hamster in Chemical Carcinogenesis Research
HOMBURGER
Syrian golden hamsters. Studies were made on exretion of both the carcinogen and the
hematite by measuring the concentration in the lungs after certain time intervals following
intratracheal injection. In the first experiment this was done after a single dose of 5 mg
BP in 45 mg of hematite. In the second experiment, a single dose was 3.4 mg, which was
given to untreated hamsters and compared with results in hamsters previously treated
once weekly for 9 weeks with doses of3 mg ofBP. The recovery values were consistently
higher for the second group, but the retention rates were similar for both groups, indicating that no metabolic adaptation occurred in the ten weeks of BP treatment. Finally,
BP recovery was compared after single doses of 23 mg, 34 mg and 0.9 mg, respectively. The
higher the dose administered, the higher was the per cent recovery of BP. This was due
to a much faster elimination rate in the first day or two for the lower two doses. After the
second day, the retention rate remained only slightly higher for the higher dose groups.
Salftotti et al. [191]: Mixed dusts, obtained by grinding together BP with iron oxide,
were suspended in saline and injected intratracheally in Syrian golden hamsters (Proc.
amer. Ass. Cancer Res. 4: 59 [1963]). Fifteen weekly injections of about 6 mg of dust (3 mg
BP) in 0.2 ml saline each, induced tumors of the tracheobronchial tree in 75% of 16 males
and 100% of 17 females examined to date; 12 brochogenic carcinomas were found in the
males and 6 in the females; they included squamous-cell carcinomas as well as some
adenocarcinomas and anaplastic carcinomas. In addition, a few adenomas were found.
Tracheal tumors included papillomas and carcinomas. The first bronchogenic carcinoma
was found 13 weeks after the beginning of treatment. Other groups of hamsters received
weekly injections of the same dose for periods of 5, 10 and 15 weeks. In addition, some
groups received a single injection of varied doses of BP. Following a single dose of about
35 mg ofBP, the first carcinoma was found at 28 weeks; following a single dose of 5 mg
of BP, no lung tumors were found in 148 hamsters examined up to 2 years. Other groups
were given varied doses of DMBA. The described method proved effective for the production and study of experimental bronchogenic carcinoma.
Salftotti et al. [192]: Grinding together a crystalline polycyclic hydrocarbon (BP
and DMBA were used) with an inert dust (iron oxide, particle size 94% < If1,) in various
proportions, results in dusts in which the particles of carcinogen and iron oxide adhere
together. These dusts are suspended in saline and injected intratracheally in hamsters
under direct visual control. The following points have been studied: 1. the rate of persistence of BP in the lung, determined spectrophotometrically, showing that single doses
of BP are almost completely eliminated within 1 week; 2. the histologic reaction in the
lung, showing a constant pattern of phagocytosis and slow clearance of the iron oxide
alone, while the addition of BP induced minimal changes in the early reaction pattern
even with Jarge doses, whereas the addition of DMBA rapidly induced severe toxic
changes; 3. long-term carcinogenesis with either single or repeated doses, which is still
in progress, but has already shown some proliferative changes of the bronchial mucosa.
-Nickel and cobalt dusts, shown to be carcinogenic by intramuscular injection (J.P.W.
GILMAN, Cancer Res. 22: 158 [1962] were also similarly studied by intratracheal administration in hamsters. A remarkable hyperplasia of the bronchial epithelium is rapidly
induced by cobalt oxide.
Smith et al. [214]: Tissue reactions to 3 types of asbestos (amosite, harsh chrysotile,
soft chrysotile) were tested by injections into the right pleural cavity of 45 golden Syrian
hamsters. Each animal received a single injection of 25 mg of one or another type of
asbestos in 0.5 cc 0.9% NaC! .... Each type of asbestos induced extensive pleural reactions
with granulomatous inflammation and wild overgrowth of fibrous tissue binding lobes of
the lung to each other, to the chest wall and diaphragm. The first such case was found
97 days after injection. Seven additional cases were found among 11 animals examined
103 to 252 days after injection. Frank pleural mesothelioma Jargely filling the thorax and
penetrating the diaphragm was found in an animal 244 days after injection of amosite.
Twenty-nine survivors are being followed for detection of any additional tumors. Results
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to date introduce the Syrian hamster as a highly sensitive species for test of biological
effects of asbestiform minerals.
Tomatis et al. [225]: This paper contains a good summary of dimethylnitrosamine
carcinogenesis in the hamster. Chronic administration of DMNA in drinking water to
Syrian golden hamsters resulted in a high incidence of liver cell carcinomas and cholangiocarcinomas. Two hemangioendotheliomas of the liver and one adenoma of the
kidney were also observed. No tracheal or lung tumors were recorded. The studies were
done on 31 females and 27 males of the Chicago University hamsters. They received
0.0025% solution in the drinking water ad libitum and 6 weeks after the beginning of the
experiment, treatment was discontinued because of diarrhea. Two weeks later, treatment
was resumed for another five weeks. The total dose each animal received was approximately 19 mg for the males and 15 mg for the females. The animals were allowed to die
spontaneously or were killed when moribund. In 31 females, there were 17 cholangiocarcinomas, 4 liver cell carcinomas and 1 hemangioendothelioma. In 27 males there were
19 cholangiocarcinomas, 7 liver cell carcinomas, 1 hemangioendothelioma of the liver
and 1 adenoma of the kidney.
WJnder et al. [234]: Pathological changes in the respiratory tract of 'smoked' C57BL
mice and Syrian hamsters were investigated. In a reduced pressure chamber animals were
exposed to smoke of filter and non-filter cigarettes, an admixture of volatile acids and
aldehydes and NOz' One group of mice was inoculated with swine influenza virus before
smoke exposure. Histological sections were taken from the nasal cavity and respiratory
tree. ... Male mice exposed to cigarette smoke and volatile agents appeared to have
increased susceptibility to nasal cavity and respiratory tree infections. Hyperplasia and
metaplasia incidence increases in 'smoked' mice and is considered secondary to inflammation. No progress of these changes occurred with prolonged exposure, not even in mice
infected with swine influenza virus. All changes were reversible. . .. Hamsters injected
subcutaneously with 8, 4, 2, and 1 mg of DENA, then exposed to smoke of non- and
charcoal-filter cigarettes and smoke free of particulate matter, developed papillary tumors
of the trachea and bronchi earlier and in greater numbers than those receiving DENA
or tobacco smoke alone. Two of 12 hamsters developed papillary growths in the trachea
after exposure to cigarette smoke .... Anatomical and histological studies of nasal cavities
of laboratory animals, in line with physical-chemical considerations, show that practically
only volatile components of tobacco smoke can pass through the nasal cavity.
Gastrointestinal Tract
Cataldo & Shklar [28]: The introduction to this paper contains a review of submaxillary
gland tumors which were chemically induced in various species. A uniform method
for the formation and implantation of pellets of powdered chemical carcinogens in the
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1. Submaxillary glands. While it is possible to induce mixed salivarygland tumors in mice by placing methylcholanthrene directly into
submaxillary glands, the only neoplasms produced in hamsters by
the direct intraglandular implantation of pellets or injection of oil
suspensions of DMBA (Me has not been studied in hamsters) are
fibrosarcomas. These submaxillary fibrosarcomas are enhanced or
inhibited by cortisone, depending on dosage and method of application, and are unaffected by vitamin A deficiency.
HOMBURGER
submaxillary salivary gland of experimental animals was developed. Thirty-four male and
female Syrian hamsters received implants of 5 mg pellets of powdered DMBA and were
sacrificed from 6-14 weeks after implantation, some animals (one-third) being allowed
to live for 8 months. There were 16 controls. Extremely large tumors were found at
sacrifice, and there were various microscopic alterations including hyperplasia, metaplasia,
connective-tissue hyperplasia and areas resembling a mixed tumor pattern. However, the
only real tumors produced were fibrosarcomas. In the hamster, the connective tissue in
the submaxillary gland is apparently the only one which undergoes malignant transformation when exposed to carcinogen.
Chaudhry & Corlin [29]: This study has been conducted with three objectives: first,
to investigate the histopathologic changes at various intervals of time in the submaxillary
gland of the hamsters following a single injection of a hydrocarbon carcinogen. For this
experiment, 50 golden Syrian male hamsters, 3 months of age, were used and were divided
into six groups. The animals were singly housed in a room maintained at 70°± 2° F and
a lighting regimen of 6 a.m. to 6 p.m. and darkness from 6 p.m. to 6 a.m. Under intraperitioneal Nembutal anesthesia, the ventral surface of the neck was opened and the
submandibular glands exposed. The right gland was injected with 0.05 cc of 0.05%
DMBA dissolved in liquid petrolatum. The left gland was used as control and injected
with the same amount of solvent. The animals from the first to the sixth groups were
sacrificed at intervals of 1,4,8,10, 14 and 18 weeks, respectively, and the glands studied
for microscopic changes. Coagulation necrosis, metaplasia of ducts, and scarring followed
by malignant changes of connective tissues were evident. At the fourteenth week, 33%
of the animals developed fibrosarcoma of various gradation. At the end of 18 weeks,
the incidence was nearly 45%. The second objective was to study the effects of different
concentrations of a single injection of the carcinogen on the number of tumors induced.
All other factors were kept constant except that 0.05 cc of 0.1, 0.25, and 1% ofDMBA
was injected into three groups of the animals, respectively. At the end of the eighteenth
week, a statistically significant difference in the incidence of tumors was apparent. Third,
study of the effect of age on the experimental induction of tumors by the chemical carcinogen was carried out. Species, sex, environmental conditions, amount and concentration of the carcinogen were all kept constant except for age. No statistical difference
in the incidence of tumors was apparent in 4 groups of animals of 1, 3, 6, and 9 months,
respectively.
Chaudhry et al. [30]: Male hamsters were given 0.05 cc of an 0.5% (250 mg) DMBA
solution dissolved in liquid petrolatum and fibrosarcomas were induced following the
injection into the submandibular glands at 3 months of age. The latency was 10 to 14
weeks. At 18 weeks, 7.7% tumors were reached, and 55% were reached when the concentration was doubled. The age of the animals up to nine months did not change the number
of tumors induced.
Chaudhry & Schmutz [31]: These studies show that neither Thalidomide nor prednisolone which, when given concurrently with 0.05 ml of a 0.5% solution of DMBA in
liquid petrolatum, had any effect on the formation of carcinomas in the injected glands.
This is in contrast to the inhibition of tumor formation observed with cortisone elsewhere.
Chaudhry et al. [32]: Eighty-two golden Syrian male hamsters, 8 weeks of age, were
divided into three groups of 50, 15, and 17 animals, respectively. The animals were
singly caged in a room maintained at a temperature of 70° ± 2° F with a lighting regimen
from 6 a.m. to 6 p.m. and darkness from 6 p.m. to 6 a.m. Under intraperitoneal Nembutal
anesthesia, the submaxillary glands were exposed. The right gland was injected with
0.05 cc of 0.5% DMBA. The left gland was used as a control and injected with the solvent
liquid petrolatum. Three days postoperatively, the animals in Group 1 were put on a
vitamin A-deficient diet and were fed ad libitum. The diet was specially prepared in bread
form and was chemically analyzed for vitamin A level. The second group of 15 animals
was given the same diet but supplemented with 1,000 1. U. of vitamin A per week. This
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group was pair-fed with the animals of Group 1. The third group of 17 animals was
given the same bread supplemented with 1,000 LV. of vitamin A per week but this group
was fed ad libitum. At the end of 18 weeks the animals were sacrificed and the number of
tumors recorded. No statistical difference in the incidence of tumor was found between
Groups II and III, and these were therefore combined for the purpose of statistical
analysis. The incidence of tumors in Group I was 25.5%, and 16% in the combined
Groups II and III. This difference was not statistically significant (P = < 32%). No
direct relationship was found between plasma vitamin A levels and liver storage. The
serum vitamin A level was maintained at near normal when the liver stores were almost
depleted in animals fed on the vitamin A-deficient diet.
Chaudhry et al. [33]: DMBA was injected into submaxillary glands in 0.5 cc of a 0.5%
solution in liquid petrolatum. Various regimens of vitamin A deficiency were tested and
no statistically significant effects were found. It may be concluded that vitamin A deficiency
does not enhance the induction of malignant tumors in the submandibular salivary glands
of the hamster when injected with chemical carcinogen.
Sabes et al. [189]: Cancer was readily induced in the hamster cheek pouch and submandibular gland by the administration of DMBA dissolved in liquid petrolatum.
Cortisone, when topically applied prior to the application of carcinogen, appeared to
enhance the incidence of tumor formation. On the other hand, when it was injected
locally into the submandibular salivary gland of the hamster prior to the injection of
carcinogen, it appeared to inhibit tumor development. The contradictory results in the
two experiments as well as in the literature could be attributed, in part, to the mode of
administration of cortisone and to the role of 24-hour periodicity in the incidence of
induced tumors.
Sabes et al. [188]: Seventy-four male golden Syrian hamsters were divided into four
groups of 20, 18, 18 and 18 animals each. The animals of Group 1 were anesthetized with
Pentobarbital sodium, the right submandibular salivary glands surgically exposed and
the glands injected with 0.05 cc of 0.025% cortisone in saline (1.2Sy). This was immediately followed by injection of the same glands with 0.05 cc of 0.5% DMBA in liquid petrolatum (2S0y). Group II animals were similarly treated by injecting 0.05 cc of the cortisone
vehicle, followed by carcinogen. Group III was injected with 0.05 cc of physiologic
saline followed immediately by 0.05 cc of carcinogen. Group IV was treated with 0.1 cc
of 0.25% carcinogen alone. One-half of each group was treated in the a.m. (9-12) and the
other half in the p.m. (2-5). Since the noncarcinogenic properties of liquid petrolatum
had been repeatedly established in this laboratory, no control for liquid petrolatum was
employed. Eighteen weeks after the injection date the animals were sacrificed with lethal
doses of Nembutal. The tumors were removed and fixed in Zenker's solution. Histologic
sections of all tumors were prepared and stained with hematoxylin and eosin. Microscopic
analysis of the tumors revealed that the group of animals treated with cortisone developed
fewer sarcomas than did the other groups. However, this intergroup difference between
the control and the experimental animals was not statistically significant (p = 0.15). When
the data were analyzed statistically by morning and afternoon grouping, it appeared that
such a difference was significant (p = < 0.05). When the animals presenting sarcoma were
noted according to time of injection, irrespective of group classification, it appeared that
the periodic distribution of induced cancers had completely obscured the effects of
cortisone. This factor may be responsible for conflicting reports in the literature of the
effects of cortisone on carcinogenesis.
Steiner [218]: DPB, BP and MC in pellet form were inserted into the submaxillary
glands of rats and mice, and MC in sesame oil was injected into the submaxillary glands
of rabbits. No hamsters were used in this study. Hemangiomas, squamous-cell carcinomas
and one adenocarcinoma (in a mouse) were produced. Sarcomas were frequent in mice
after MC, and occasionally occurred in rats (BP). In mice, there were occasional 'mixed
tumors' following MC
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HOMBURGER
Della Porta [41]: Administration by stomach tube of 36 to 50 doses of 5 mg of MC
in corn oil to Syrian golden hamsters of the Abrams Small Stock Breeders, Chicago,
Illinois, or to animals of the author's own laboratory produced squamous-cell tumors of
the forestomach, adenocarcinomas of the small and large intestines, adenocarcinomas of
the mammary glands, teratomas of the ovaries and sebaceous tumors of the skin and ear
duct glands. Of these types of tumors, only a few squamous-cell papillomas of the forestomach were observed in control animals. Inflammatory lesions of the intestine with
hyperplastic and atypical glands were a common finding in both the experimental and
control groups. (The absence of gastrointestinal tumors in the control animals contrasts
with the high frequency of such tumors in the colony of Fortner.)
Fortner [68]: This report, which is preliminary, deals with 620 Syrian hamsters
obtained from a commercial dealer. Observations showed that of 292 animals dying when
from 251 to 881 days old, 36.5% (107 animals) had tumors of the colon; 69 animals (23%)
had malignant tumors; 26 (9%) had only benign polyposis of some gastrointestinal
segment; 12 (4%) had other benign tumors. Cystadenomas, adenomas and other cysts of
the liver, sebaceous-gland adenomas, cellular blue nevi and hemangiomas of the spleen
are representative of those benign tumors which were frequent, but not included, in any
of the statistics. There were primary adenocarcinomas of the glandular stomach, small
intestine and large intestine in 28 animals, some associated with benign polyposis. In an
additional 40 animals, there was adenomatous polyposis, predominantly in the colon.
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2. Stomach and intestines. According to STEWART [219], there is
no species of laboratory rodent in which gastric cancer appears
regularly or with sufficient frequency to warrant an attempt to develop
a high gastric-cancer strain. The mastomy, or multimammate mouse,
presents an exception. However, this rare animal, which was first
found to have gastric cancer in South Africa (an observation later
confirmed in the USA), is not generally available. If recent observations made in hamsters are correct, then a significant incidence of
gastric and intestinal cancers occurs spontaneously in Syrian hamsters
from certain sources. Tumors of the colon, forestomach, glandular
stomach, small intestine and large intestine have been reported from
at least two laboratories. In our own hamster colony, no gastrointestinal
neoplasms exist. Adenocarcinomas of the forestomach and the small
and large intestines have been induced by orally administered Me
and BP and have been observed (epithelial tumors of forestomach)
after painting DMBA onto the cheek pouch.
Papillomas of the forestomach and adenomatous polyps of the
colon have been seen in hamsters fed N-2-fluorenylacetamide and
o-amino-azotoluene as well as after ingestion of urethane. With Nnitro-N-methylurethane, multicentric epithelial tumors of the gastrointestinal tract have been observed.
These scattered and fragmentary observations suggest that a
systematic study of chemical carcinogenesis in the gastrointestinal
tract of hamsters may be worthwhile.
The Syrian Golden Hamster in Chemical Carcinogenesis Research
197
There were two leiomyosarcomas of the colon and one angiosarcoma of the colon.
Adrenal cortical carcinomas were found in 7, and adrenal cortical adenomas in 8 animals.
There were numerous instances of adrenal cortical hyperplasia, cancer of the ovary in 7,
cancer of the endometrium in 3, leiomyomas of the uterus in 2, bile-duct or hepatic-cell
cancers of the liver in 10. Cancer of the kidney and pancreas were found in 2 animals each.
Islet cell adenomas and lymphosarcomas were present in 3 and 8 animals, respectively.
There were malignant melanomas in 8, cancer of the thyroid in 2 and cancer of the lung
in 3. Two or more different primary tumors were found in 10% of the tumor-bearing
animals. This study indicates a frequent occurrence of spontaneous gastrointestinal
neoplasms in these particular hamsters.
Fortner [67]: These are observations on 301 hamsters surviving for 20 to 23 and a
half months. Spontaneous adenomatous polyps and cancers of the gastrointestinal tract
were noted and also a few transplantable malignant melanomas. There was a considerable
incidence of chronic endocrine disfunction, as indicated by adrenal cortical alterations,
ovarian luteinization and testicular atrophy. There was also liver and kidney damage.
Carcinogenesis appeared to be potentiated by subcutaneously injected bile.
Fortner [69]: In FORTNER'S experience, neoplasms of diverse origin were found in
81 (90%) of 94 control males and 60.9% of 87 control females. Multiple types of tumors
originated in a single animal. In the controls, 43.6% of the males and 20.7% of the females
were so affected. Castration of the young sexually mature hamster had several effects on
the development of spontaneous tumors. There was a significant decrease in the incidence
of neoplasms of the gastrointestinal tract and accessory structures. There was complete
suppression of the development of tumors of the secondary reproductive organs. Stimulation of the adrenal cortex followed castration in males, but not in females. Also noted
was that this extremely high incidence of spontaneous tumors appears to be unique to
FORTNER'S strain [see also 154].
Patterson [154]: Of 370 hamsters carrying a subcutaneous or cheek-pouch transplant
of a human transverse colon carcinoma and being conditioned by 2.5 mg twice weekly of
subcutaneous cortisone, four developed carcinomas of the small intestine. These animals
had been transplanted with the human tumor at age 2 months or less, and the hamster
tumor of the duodenum appeared between 21 to 56 days thereafter, and in all animals
before the age of 5 months. Spontaneous incidence of these tumors in the strain used was
absent, except for one cancer of the small intestine in an animal bearing a transplant of a
human fetal ovary. There was also one adenoma and adenomatous hyperplasia of the
duodenal mucosa in 15 animals out of about 200 studied. While the authors are convinced
that development of the duodenal cancers observed is directly related to the presence of
the growing human cancer in the animal, it is questionable whether the study is well
controlled with regard to the effect of the cortisone administration alone.
Snell [215]: In 90 male and 78 female mastomys aged from 12 to 35 months, neoplasms
of the glandular stomach (carcinoma and precancerous lesions) were found in 48% of
the males and in 23% of the females. In OETTLE'S (Johannesburg) original observation
of cancer of the glandular stomach, 62% of the females and 37% of the males had cancer.
The reasons for these contradictory sex incidence figures are not apparent. (Note: This
does not concern hamsters, but refers to mastomys [see also 219]).
Stewart [219]: This is a general review on experimental carcinoma of the stomach
and refers to FORTNER'S paper on primary adenocarcinoma of the glandular stomach,
small intestine and large intestine in 14 of 223 Syrian hamsters between the ages of 251
and 715 days. There is some qualification in STEWART'S mind, because he specifies that
FORTNER did not illustrate his observations in the paper quoted [67].
See Toth et al. [226], p. 175.
gallbladder produced a high incidence of adenocarcinoma. A choles-
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3. Gallbladder, biliary tract: The implantation of MC pellets into the
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Bain et al. [15]: MC pellets were placed in the gallbladders of fifty hamsters. In 25
animals, estradiol was also implanted subcutaneously. Thirty-nine hamsters survived
longer than one month. During 60 to 240 days, 31 neoplasms developed in 28 of the
animals; 24 were biliary carcinomas; 5 were sarcomas of the body wall; 2 were mammary
carcinomas. Three hamsters had both biliary carcinomas and sarcomas of the body wall.
Estradiol did not influence the development of the biliary neoplasms in these male
hamsters.
Bain & Kowalewski [16]: This report refers to a previous paper by the same authors
[15]. This is an anatomical study of tumors of the gallbladder induced by the insertion of
pellets of MC into the gallbladder. More than 70% of the experimental animals developed
carcinoma in that organ within 400 days of implantation. In those surviving for more
than 140 days after pellet implantation, tumor incidence was 77%; after 240 days, 81 %.
There were various changes in the liver of these hamsters. There were, in numerous
instances, metastases to distant points and lymph nodes, also to the gastric wall, the
diaphragm, the lungs and the pleura. Successful transplantations into the cheek pouches
of hamsters were made with subsequent retransplantations which unquestionably induced
malignant invasive papillary adenocarcinoma of the gallbladder.
Bain et al. [17]: Insertion of MC pellets into the gallbladder was supplemented by
high-cholesterol diets. Eighty-three % of these high-cholesterol-fed animals developed
cancer, in comparison with 57% in animals on the control diet. Intrahepatic implantation
of MC pellets caused a few sarcomas with the high-cholesterol diet.
Fortner [66]: It is concluded that the biliary-tract carcinoma may be caused by
carcinogen in the bile, since primary adenocarcinomas of the small intestine with regional
lymph node metastases were induced in three hamsters having received subcutaneous
injections of bile from a living patient with cancer of the extrahepatic biliary tract. A
fourth animal had a leiomyosarcoma of the colon. Adenocarcinomas of the bile-duct
type were found in the liver of two hamsters in the previous experiment. Precancerous
lesions, extensive proliferations, cellular hypertrophy and distinct atypia of the intrahepatic
bile duct have been observed. To date, these findings have not been present in control
animals. (In view of the high incidence of gastrointestinal cancer in FORTNER'S colony,
this interpretation is subject to serious question.)
Fortner [65]: Bile was obtained from a man and a woman who had anatomically and
histologically proven cancer of the common bile duct. Three times each week a small
portion of frozen bile was chipped off, allowed to remain at room temperature until
melted, and then injected subcutaneously into the interscapular region of 20 Syrian
hamsters and 40 milk-factor-free C3H mice. This was done at weanling age, beginning
with 0.1 to 2.0 cc for hamsters, and being increased to 2.0 and 4.0 cc. The surviving
animals were injected for as long as 16 months. Two hamsters dying the fifteenth and
sixteenth months of the experiment showed tumors 0.8 to 4 cm in diameter in the liver
which, histologically, were adenocarcinomas arising from the bile-duct epithelium.
Unfortunately, these were the only hamsters surviving for twelve months or longer in
which histological examination was feasible.
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terol-rich diet acted as a promoter in this carcinogenesis system.
N-2-fluorenyl-acetamid and DMNA were capable of inducing 'cystic
dystrophy' and cholangiocarcinomas.
It is difficult to decide whether the bile-tract carcinomas and other
cancers observed by one group of investigators following injection
of bile from patients with cancer of the bile duct were, in fact, induced
or spontaneous tumors, and if they were induced, whether this was
an instance of chemical or viral carcinogenesis.
The Syrian Golden Hamster in Chemical Carcinogenesis Research
199
See Argus & Hoch-Ligeti [9], p. 187.
Della Porta et al. [46]: Carbon tetrachloride was administered by stomach tube to
10 females and 10 male Syrian golden hamsters in weekly doses of 6.25 to 12.5y for 30
weeks. There was post-necrotic cirrhosis, with regenerative hyperplastic nodules in
animals that died during or after the period of treatment. All animals, 5 males and 5 females, dead or killed 25 to 30 weeks after the end of the treatment, had one or more
liver-cell carcinomas. No cholangiomatous tumors were observed. The induction with
AAF, of only cholangiomatous tumors, and with carbon tetrachloride, of only liver-cell
tumors, is discussed. This points out a difference between rats, in which both types of
cancers are found--cholangiomas and hepatomas-and the hamster, in which different
types are apparently produced.
Della Porta et al. [45]: AAF is one of the most versatile carcinogens and has been
tested in many species. So far, only one brief study in the hamster by PASCHKIS has produced cholangiomas. In this case, the AAF was administered simultaneously with stilbestrol
[153]. Also, DONTENWILL AND MOHR [51] have produced cystic lesions in the liver by
feeding this carcinogen with estrogen. In the present study, it was fed at the 0.04% level
in the diet to male and female Syrian golden hamsters for 40 or 26 weeks. A high incidence
of benign cholangiomatous lesions and some cholangiocarcinomas were seen. Outside of
the liver, only one colonic adenocarcinoma, 1 leiomyosarcoma, and 1 generalized lymphoma that were not believed to be related to the experimental diet were observed. No
parenchymal liver-cell tumors were observed. No definite differences between the male
and female response were noted. These widely different findings by three different authors
using the same carcinogen under comparable and different conditions would suggest that
perhaps the difference in their observations may be due to differences in the genetic
background of the hamsters, which is unknown in all these experiments.
Dontenwill & Mohr [50]: This paper reports on electrophoretic observations of the
blood of hamsters suffering from the earlier described cystic dystrophy of the liver
induced by estrogen and AAF. Paper electrophoretic studies showed that the average
value of globulin in 12 animals was nearly twice as high as that in the controls and that
there was a marked reduction of albumin in these animals. This is much like observations
in humans with liver disease.
Dontenwill & Mohr [51]: This is a study on hepatic changes in animals treated with
estrogen and also on a series of animals receiving estrogen and AAF. In these animals
there was marked enlargement of the liver with a multi-cystic disease, and adenocarcinoma
of the liver. It appears that the estrogen-treated hamster reacts differently from the rat to
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4. Liver. Hepatomas have been caused in hamsters by feeding
carbon tetrachloride, o-aminoazotoluene, AAF, DENA, DMNA, estrogens, naphthylamine and benzidine.
Azo-dye carcinogens appear to be less carcinogenic for the hamster
liver than they are for rats, and chemical studies show that hamsters
metabolize this type of compound in a fashion closely related to that
seen in dogs, rabbits, cats, monkeys and man. Estrogens appear to
facilitate hepatic carcinogenesis, and testosterone has inhibiting effects.
In isolated instances, hepatomas have developed in castrated male
hamsters given estrogens for prolonged periods of time. Nitrosamines
have produced liver cancer in hamsters under some conditions and
only cirrhosis under other circumstances. However, because of many
variables, these studies are not comparable.
HOMBURGER
the AAF; it also appears that the estrogenic hormones act synergistically in producing this
disease picture.
Dontenwill & Mohr [53]: During treatment with a cirrhosis-producing diet and also
during treatment with dimethylaminoazobenzol in Syrian hamsters, hepatic cirrhosis
was not produced. AAF, on the contrary, shows a strong proliferative action upon the
biliary ducts. This proliferative action is inhibited by testosterone and aggravated by
estrogen. The latter treatment leads to cystic livers without, however, carcinoma formation. During the treatment with DENA, the estrogens also show a proliferation-promoting
action upon the biliary tract. This action is not evident on the carcinogenic effect of
DENA in the bronchial epithelium. Apparently, estrogens have their carcinogenic effect
only in those tissues in which they also have proliferation-promoting effects.
See Dontenwi!! & Mohr [49], p. 188.
See Herrold [83], p. 189.
See Herrold [82], p. 190.
Herrold [86]: Two groups of animals were used, consisting of 16 animals each of
both sexes. They were starved from 4: 00 p.m. through the next morning. These animals
received by stomach tube 0.4 ml of the test substance, corresponding to 0.8 mg of the
N-nitroso-N-methylurethane, at weekly intervals for 2 months and then twice a week for
4-5 months. The control group received an 0.5% solution of aqueous ethanol. Necropsies
were performed on all animals killed or found dead and the results are tabulated. The
16 treated hamsters had hyperplasia in all esophagi, epidermoid carcinomas in 13 out of 16,
hyperplasia or papillomas in the forestomach of all animals, and also epidermoid carcinomas in all animals. The pharynx of nine animals showed hyperplasia and epithelial
atypism. There were two ovarian thecomas, two cases of stromal hyperplasia of the
uterus and one case of hyperplasia and papilloma of the vagina. Tumors that formed in
the esophagus, stomach and forestomach were diffuse and multicentric in nature, suggesting that the mode of action was not a local one. N-nitroso-N-methylurethane releases
diazomethane in alkaline solution, and subcutaneous administration of this compound to
mice and rats induces acute and chronic lesions in the lung. This has also been found in
Syrian hamsters. While no unequivocal carcinomas have been found in the lung, there
were numerous benign tumors. Neither the original carcinogen, N-nitroso-N-methylurethane, nor the diazomethane exerts its action locally subcutaneously; rather, they do
so in the lung, where they are metabolized. In analogy, it is concluded that in the gastrointestinal tract also, carcinomas occur at the site of excretion or metabolism of the carcinogen. As yet, the mechanism of carcinogenesis and the reasons for selective organotropic effects of nitrosamines are unknown. There are marked differences in the local
effects between N-nitroso-N-methylurethane and N-nitroso-N-methylurea, although
the sites of action have certain similarities.
See Herrold & Dunham [88], p. 191.
See Herrold & Dunham [89], p. 191.
Maluguenna [130]: The author states that 2-acetylaminofiuorene called forth tumors
in 4 Syrian hamsters out of 17 taken into experiment or of 10 that had been living for a
year or more. Those tumors were: multiple skin papillomas in one case and liver tumors
of different structure in three cases.
Miller & Miller [136]: This paper gives an extensive biochemical discussion of the
carcinogenic mechanisms of diazo-dyes. It is pertinent to the hamster only in that it states
that 4-dimethylaminoazobenzene resulting nearly invariably in liver tumors in rats will not
produce such tumors in the hamster. AAF, which also gives a high incidence of liver
tumors in rats when fed from 4 to 5 months at 0.25 to 0.05% of the diet, will cause
liver tumors in hamsters; however, the hamsters are much less susceptible than the rats.
Carbon tetrachloride and chloroform are listed as inducing hepatomas in mice but not
in rats, and there is no note made here that carbon tetrachloride, as stated by SHUBIK [193]
and his group, also induces liver cancer in the hamster.
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200
201
Miller et at. [137]: N-hydroxy 2-acetylaminofluorene (N-hydroxy AAF, a proximate
carcinogenic metabolite of AAF in the rat) produced tumors at sites of local applications,
i.e., the forestomach, on oral administration and sites of injection in the mouse and hamster, whereas AAF was inactive at these sites. At other sites, the liver, mammary gland
and urinary bladder in the mouse and the liver in the hamster, AAF and its N-hydroxy
metabolite had equal carcinogenic activities. When treated topically with croton oil,
mice fed AAF had a higher incidence of skin papillomas than did mice fed N-hydroxy
AAF, both the mouse and hamster N-hydroxylate AAF in vivo. AAF is not carcinogenic
in the guinea pig and no N-hydroxylation of AAF has been detected in this species.
However, administration of N-hydroxy AAF to guinea pigs resulted in adenocarcinomas
of the small intestine upon feeding and sarcomas upon injection. The comparative
carcinogenicities of AAF and N-hydroxy AAF in the mouse, hamster and guinea pig
provide further evidence that N-hydroxy AAF is a proximate carcinogenic metabolite
of AAF in those species in which AAF is carcinogenic.
Mohret at. [141]: The action of DENA was tested on pregnant golden hamsters. After
administration of doses totaling 0.002-0.014 g (daily dose, 0.002 g) during pregnancy,
the young were examined at various intervals after birth. At 25 weeks after birth, 42%
of the animals exhibited tracheal papilloma, some multiple. Of the treated mothers, 73%
developed tracheal papilloma, again partly multiple, 25 weeks after the first administration
of the drug. Within the same interval, 88% of the young and 71% of treated mothers
showed alterations of the liver with varying changes in parenchymal structure. When
newborn hamsters from treated and untreated mothers were exchanged, only the young of
treated mothers developed papilloma. The passage of DENA through the placenta after
intracardial injection of the drug was proved by thin-layer chromatography. The resulting
injury to the liver (cirrhosis) is also revealed by reduced incorporation of P32. The key
conclusions were that the placenta has no protective function against carcinogens of this
nature and that mothers' milk obviously contains no amount of carcinogenic matter
sufficient to induce demonstrable changes in the young animal.
Paschkis et at. [153]: Previous work from this department has shown that prolonged
estrogen administration induces in the hamster cystic hyperplasia of the endometrium
[164]. This lesion in women is frequently considered to be precancerous. However,
no endometrial cancer was observed in hamsters exposed to diethylstilbestrol for as long
as 8 months. We then attempted to induce endometrial cancer by simultaneous treatment
with diethylstilbestrol and with AAF (0.03% in diet). However, no malignant changes
were seen in the endometrium of animals treated up to 8 months .... In many of these
hamsters, liver tumors developed which, on histological examination, were shown to be
pure cholangiomas, whereas the AAF-induced liver tumors in rats are usually of the
mixed hepatoma-cholangioma type. These tumors have been transplanted subcutaneously
into female and male, otherwise untreated hamsters. In one female hamster treated with
stilbestrol alone, a kidney tumor was found; kidney tumors usually develop only in
estrogen-treated male hamsters.
Saffiotti et at. [193]: Since bladder cancer in animals previously had been produced
only in the dog, the use of other species is important. It was found by SAFFIOTTI et at.
that o-aminoazotoluene induced in hamsters, in addition to liver-cell tumors, a high
incidence of tumors of the urinary bladder [224]: Because of this observation, a series
of aromatic amines were tested as follows: 1. 2-naphthylamine, 2.1-naphthylamine,
3. benzidine, 4. benzidine dihydrochloride, 5.3,3-dichlorobenzidine (40% as dihydrochloride, 60% as free base), 6. o-toluidine, 7. o-dianisidine, 8. 4-aminodiphenyl. These
chemicals were given at an 0.1% weight/weight concentration in the diet to groups of
Syrian golden hamsters for their life-span. There were eight groups of 30 males and
30 females and a ninth control group receiving only the diet. The results were that
2-naphthylamine in concentrations of 1 % caused a high incidence of bladder tumors-l0
out of 23 males and 8 out of 16 females had bladder tumors-almost all typical transitional
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The Syrian Golden Hamster in Chemical Carcinogenesis Research
HOMBURGER
cell carcinomas. The first one was found in a male dying at 45 weeks and in a female
dying at 49 weeks. Benzidine-treated animals developed extensive bile-duct proliferations
and cysts with cholangiofibrosis and with a very high incidence of liver tumors. This
was also true for the benzidine dihydrochloride. In the naphthylamine-treated groups,
there were one male and one female with hepatomas. In conclusion, at the level of 0.1 %
in the diet, the same as that used for o-aminoazotoluene, benzidine and benzidine dihydrochloride induce marked carcinogenic response in the liver of the hamster with liver cell
tumors and cholangiomas, but no response occurs in the bladder. The other amines are
essentially negative. At the dose at which benzidine is highly carcinogenic for the
hamster, 2-naphthylamine appears ineffective. At a much higher dose, that is, 1%, 2naphthylamine produces a high incidence of bladder tumors, mostly transitional cell
carcinomas, and appears to have weak activity in the induction of hepatoma.
Seal & Gutmann [204]: This paper deals with a study of the ability of various animal
species to hydroxylate the carcinogen, AAF, and it was found that of those species
examined, the hamster liver yielded the most active preparations ofhydroxylating systems.
The data suggested that there exist separate enzymes for ortho- and para-hydroxylation.
Shubik et al. [212]: This is a review of the authors' various carcinogen experiments
involving DMBA, BP, MC, DBA and BA; also AAF, urethan, carbon tetrachloride and 4dimethylaminoazobenzene. The tumors observed included tumors of the liver, skin,
respiratory tract and gastrointestinal tract and miscellaneous other tumors. There are
essentially three types of action by the compounds tested: First, there are compounds
such as AAF, which merely enhanced the incidence of tumors that are commonly seen in
control animals. Second, there are compounds, such as carbon tetrachloride, that produce
a solitary type of tumor in one organ, these being of a type never observed in the controls.
Third, there are those compounds, such as urethan and orthoaminoazotoluene, that
combine the two actions described above, producing tumors of types that are rare or
absent from the controls, as well as enhancing the incidence of commonly occurring
spontaneous tumors. The complexity of the problem is discussed, and it is pointed out
that there may be extraneous contamination with environmental carcinogens such as
are introduced by food or air, etc., which change the response of these animals to various
carcinogens. (Note: There are important hereditary factors which are not discussed by
these authors.)
Terracini & Della Porta [222]: Male and female Syrian golden hamsters received 6.25
microliters of carbon tetrachloride by stomach tube weekly for 30 weeks. All the animals
surviving at least 3 months after termination of the treatment developed benign or
malignant liver cell tumors, one with metastases. Portal fibrosis and regenerative nodules
occurred commonly, but no cholangiomatous tumors were observed. This contrasts
sharply with our finding that AAF induced only cholangiomatous tumors in this species.
The biological differences between various species in their response to liver carcinogens
and the histogenesis of liver tumors will be discussed.
Tomatis et al. [224]: Administration of 0.1 % o-aminoazotoluene in the diet for 49
weeks to Syrian golden hamsters resulted in the occurrence of liver-cell and urinary
bladder tumors in 45% and 50% of the animals. No definite sex difference could be
established. In addition, 3 mammary adenocarcinomas from 15 females are believed to be
related to the treatment. A similar relationship for other tumors seen could not be established with certainty. The hamsters used in these studies came from the Abrams Small
Stock Breeders in Chicago, Illinois, and were 12 to 14 weeks old at the start of the experiment. In the untreated hamsters the following tumors were found: cholangiomas,
papillomas of the forestomach, malignant lymphomas, one carcinoma of the salivary
gland and one plasmocytoma in a male. There were no urinary bladder, liver-cell, gallbladder or mammary tumors. Other tumors seen in the treated animals which cannot
definitely be related to treatment were malignant melanoma of the skin, papilloma of the
forestomach, malignant lymphoma, adenomatous polyp of the colon, hemangioma of
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The Syrian Golden Hamster in Chemical Carcinogenesis Research
203
the liver, 3 of the spleen and one of the brain, as well as polycystic lesions of the pancreas.
Apparently, this hamster strain shows a relatively high incidence of tumors after age
approximately 60+ weeks.
See Tomatis et at. [225], p. 193.
Weisburger et at. [232]: Three 6-month-old male hamsters and three 4-month-old
female hamsters were given intraperitoneal injections of a suspension of N-2-fluorenyl9-C14-acetamide in isotonic saline gum acacia solution at the level of 50 mg/kg body weight.
The animals were caged singly and urine and feces were collected separately. At the end
of two days they were killed and various organs were studied. Noteworthy is the predominance of the formation and excretion of glucuronic acid conjugates which are
eliminated chiefly in the urine. In this regard, the hamster is like the guinea pig. Furthermore, the hamster converts substantial amounts to the N-hydroxy derivative. This is
thought to be a necessary metabolite which may lead to the active carcinogen. The rat
generally forms only small amounts of this metabolite and in this respect, the hamster
resembles the dog, rabbit, cat, monkey and man. The higher amount of protein-bound
radioactivity in the male hamster, as compared to that in the female hamster, is possibly
related to the higher susceptibility of the liver in the males.
1. Kidney. Prolonged administration of estrogens in doses of at
least 54 mg of stilbestrol (0.6 mg every other day) caused, in the male
hamsters only, neoplasms of the kidney, which remain hormonedependent upon transplantation. There are marked changes in the
pituitary of estrogen-treated hamsters such as chromophobe adenomas
and a marked drop of pituitary luteinizing hormone content. However,
it is not clear whether the carcinogenic effect of estrogen upon the
kidney is mediated via the pituitary.
Kidneys transplanted from males or females into the subcutaneous
tissue of estrogen-treated males develop tumors with equal frequency.
The factor that, in the female, prevents the estrogen from causing
renal carcinomas appears to be progesterone. After serial transplantations the estrogen-induced renal tumors may attain autonomy and
grow in untreated male or female animals.
Partial nephrectomy or trauma to the kidney facilitated the induction of renal neoplasms in estrogen-treated males. Tissue-culture
studies have shown that the hormone dependence of the tumors is
due to stromal factors and not to any characteristics of the renal cells
themselves.
2. Urinary bladder. Orthoaminoazotoluene given in the diet at the
0.1 % level for 45 weeks led to urinary bladder cancer in about half of
the treated hamsters. Recently, much higher doses (1 %) of s-naphthylamine caused occasional bladder cancers in male and female hamsters.
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Urinary Tract
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HOMBURGER
Algard [4]; Three sex hormone-dependent hamster tumors have been investigated
in dispersed cell and organ-culture systems. Tumor cells emigrate from primary explants
and established outgrowths, exhibit growth (mitosis), and may be passaged serially in
hormone-free medium. Incorporation of hormones into the culture medium, either
initially or after an outgrowth is already established, fails to elicit any deflection from the
patterns of behavior observed in untreated cultures. Cultures of a renal carcinoma and a
trichoepithelioma, when reimplanted into animals, have grown only in the presence of
appropriate exogenous hormones. In organotypic culture, behavior of these tumor
tissues with respect to hormones is unlike that observed in cell cultures. The renal carcinoma and a leiomyoma rapidly deteriorate in hormone-free media; the trichoepithelioma,
however, shows appreciable survival after one month in hormone-free organ culture,
but without mitoses. In the presence of hormone(s) all 3 tumors show enhanced survival
and mitoses occur. The capacity of these neoplasms to respond to hormonal excitation
appears to be related to tissue integrity. If the architectural pattern of the tumors is
destroyed, as in dispersed cell culture, a state of reversible 'autonomy' seems to be
achieved. Direct versus indirect hormone-tumor cell relationships in these neoplasms are
discussed and a brief description is given of these tumors in vivo.
Aigard [2]; Evidence derived from tissue-culture studies of an estrogen-induced
dependent neoplasm of the kidney and an androgen-estrogen-induced dependent tumor
of the flank organ in Syrian hamsters suggests that both are of epithelial origin. Cells
from these hormone-dependent tumors can be grown in hormone-free media; the addition
of crystalline hormone does not enhance growth or survival. However, when the kidney
tumor is cultured as an 'organ' fragment, growth does not occur, and survival time is
greatly reduced unless estrogen is present in the culture medium. Responses to doses of
5, 10, and 25 fig of diethylstilbestrol per ml of culture medium indicate a graded effectmore mitoses occur at the higher value.
Arcadi [8]: Cells which contain glycogen are demonstrated in estrogen-induced
renal tumors (this is claimed to be the first such demonstration). These cells appear to
arise from connective-tissue cells.
Bloom et al. [22]: Estrogen-induced kidney tumor was used for transplantation into
young male hamsters after various ablative measures. Bilateral adrenalectomy produced
reduction in the tumor growth rate. A much more pronounced effect was achieved by
orchidectomy, which completely inhibited the development of tumor grafts. Orchidectomy
in hamsters already adrenalectomized and showing some degree of tumor inhibition
produced further inhibition. The administration of estradiol monobenzoate or testosterone
propionate completely neutralized the tumor-inhibitory effect of orchidectomy. It was
concluded that this tumor is dependent upon estrogen derived principally from the
testes, either directly or by the conversion of testosterone.
Bloom et al. [23]: This is a lengthy review article which, in addition, reports on
experimental work on a transplantable renal tumor in young male hamsters which is in
the 21st to 35th generation and is independent of exogenous estrogen administration.
A synthetic oral progestational agent, 6(a)-methyl-17(a)-hydroxyprogesterone acetate
(Provera) in doses of 2.5 mg subcutaneously 3 times weekly had no effect on tumor
growth, compared with untreated controls. Testosterone propionate in similar dosage
also had no effect. On the other hand, a marked inhibitory effect was seen in the tumors
of those animals treated with cortisone in doses of 1.25 to 2.5 mg subcutaneously 3 times
weekly, the reduction in tumor growth rate being greater with the larger dose. This was
not dependent on general toxic manifestation and it appeared to be specific for kidney
tumors because other transplanted tumors, such as polyoma-induced kidney tumors and
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This is of interest, since naphthylamine has been implicated in human
urinary bladder cancer and naphthylamine bladder cancers have been
produced in dogs, but so far not in rodents other than the hamster.
205
non-renal tumors, did not respond. The most marked inhibition occurred with the
combination of cortisone and Provera, with practically complete inhibition of tumor
growth. The relationship of these observations to treatment of renal carcinoma in man
is discussed. It is to be noted that these studies deal with a basically autonomous tumor
which appears not to be dependent on estrogenic hormones any more. There is no mention
of hypophysectomy as a hormone imbalance.
Burrows [27]: BURROWS notes the failure of most investigators to produce cancers
of the kidney with estrogens, which is opposed to the remarkable observations of MA TTHEWS, KIRKMAN AND BACON and others on the induction of carcinoma of the hamster
kidney by estrogen [133].
Dontenwill [47]: This is a review of KIRKMAN'S work; in addition, the author reports
on his own observations-that about 60% of castrated estrogen-treated males showed
kidney tumors with peritoneal metastases. Histologically, these tumors were partly of a
hypernephromatous and partly of a sarcomatous nature. It appears that some of them
are derived from tubular epithelium. On the other hand, in one case of a widely metastasizing tumor, there was a typical fibrosarcoma with collagenous fibrils and argyrophilic
fibrils. In one-third of all treated animals, large adenomas of the pituitary were seen to
contain granulated basophiles, amphophiles and also Crooke cells. In about 50% of the
animals there were parenchymatous changes of the liver, which corresponded to a cirrhosis, with proliferation of the bile ducts. Some of these were considered as early hepatic
carcinomas. In two animals there were adenocarcinomatous-type hepatic carcinomas
which were transplantable and which were definitely different from the renal tumors.
While the kidney tumors were hormone-dependent and grew only in animals treated with
estrogens, this was not the case for the liver tumors. It is to be noted that the observation
of liver tumors under hormonal treatment such as the estrogen used here is unique and
may be a genetic characteristic of the hamsters used by DONTENWILL.
Dontenwill & Eder [48]: This is essentially a duplication of earlier work by KIRKMAN, BACON, HORNING AND WHITTICK and others on estrogen treatment for prolonged
periods in golden hamsters, and on the production of kidney tumors in the males.
The difference here was that the animals received the estrogen as diethyl-dioxystilbain
(Bayer) in daily doses of 0.6 mg in sesame oil intermuscularly. In 86 of 300 9-month-old
animals the usual nodular kidney tumors were found after 8 months of treatment. These
were transplantable, with relatively short latency periods of only two weeks in animals
which were also treated with estrogen, like the donor animals. This is in contrast to
HORNING'S much longer (3 to 7 months) time of latency. A noticeable difference with
other investigators was the appearence of amyloidosis in liver, kidney, adrenals and spleen
in 43 of 86 animals with tumors. This may indicate a strain susceptibility to amyloidosis
in this case. Another complication not observed by others was the high incidence of liver
cirrhosis with cholangiocellular carcinoma in two cases and an adenoma of the liver in
one case. There were no relationships of these latter changes to the dosage. The same
hypophyseal adenomas as described by other authors in the prolonged treatment of
hamsters with estrogen were also found.
Dontenwill & Ranz [60]: In previous work the author has shown that estrogeninduced kidney tumors of the hamster are only transplantable into animals which are also
treated by estrogen and that there is a dose-response relationship between takes and estrogen
dosage. This is in contrast to renal sarcomas induced by BP. In the present paper, castrated
male recipients of estrogen-induced, transplanted kidney tumors received growth hormone (1 mg) which produced, during 4 months of daily injections, an increase of about
78%, compared to 13% body weight in the controls. In spite of this marked growth
hormone effect no takes were observed, demonstrating again the dependence of these
tumors on another hormone, namely, estrogen.
Dontenwill & Wrba [62]: Organ cultures were made of small tumor fragments
and it was already evident after 48 hours that there is a separation into stroma (fibroblasts)
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The Syrian Golden Hamster in Chemical Carcinogenesis Research
HOMBURGER
and tumor cells which remain in the center of the organ culture. When normal hamster
serum is added to the culture, the central tumor portion does not survive long, whereas
when estrone sulfate is added to the normal hamster serum in concentrations of 5 X 10-6 to
5 X 10-9 , these tumor centers of the cultures are preserved. When serum of estrogen-treated animals is added, the same phenomenon takes place. Apparently, the estrogen acts
in the tissue culture, directly stimulating the central tumor core. Following transplantation
of the tumor core alone into a new culture, a narrow edge of fibroblasts forms and if this
procedure is continued, several transfers lead to death of the culture. The addition of
estrogen does not prevent this transfer necrosis. There appears to be an interdependence
of the tumor cells with normal fibroblasts, as described for other tumors.
Guthrie [78]: The origin of tumors in the kidneys of male golden hamsters that have
carried a subcutaneous pellet of diethylstilbestrol for several months has been restudied
because of conflicting reports. Kidneys of 38 male hamsters implanted with pellets (12 mg)
of diethylstilbestrol at 4 weeks of age and reimplanted at intervals of 6 months have been
compared microscopically with those of control male and female hamsters of appropriate
ages from 5 to 53 weeks .... Chronic pyelonephritis is found to be characteristic of the
kidneys in both male and female hamsters from the 8th week and tubule atrophy increases
with age. Coincidentally, diapedesis occurs between the arciform vessels, especially where
interlobular vessels arise. In females the extravascular blood cells spread peripherad
among the shrunken tubules but in control males there is little spread .... Pyelonephritis
is not aggravated in the estrogen-treated males. The multicentric solid adenomas found
in these animals arise from epithelium of atrophying proximal convoluted tubules located
deep in the cortex near nests of extravascular basophilic elements that spread in these
males as in the control females. Changes in cells of these proximal tubules as they respond
to the atypical stimulus of estrogen and give rise to tumors are described. The occurrence
of renal tumors in estrogenized male hamsters is another example of the correlation between local cellular imbalance and tumorigenesis.
Horning [96]: This is a good review (up to 1956) of the hormonal factors necessary
for the formation of kidney tumors in hamsters and a study on the effects of testosterone.
Male golden hamsters of indeterminate ancestry were used in this experiment. Sixty
hamsters, 8 to 10 weeks of age, were divided into 3 groups; the first group received
stilbestrol alone; the second group, combined treatment with stilbestrol and testosterone
propionate; the third group was untreated. Pellets of 20 mg of pure diethylstilbestrol
were used, and the incidence of tumors could be greatly increased by giving a second
pellet 3 to 4 months after the first one. The testosterone was given as testosterone propionate. From the age of 2 weeks, hamsters of group 2 received a weekly intramuscular dose
of 2.5 mg in peanut oil, and this was continued throughout the experiment. Tumor transplantations were done into untreated and estrogen-treated hamsters. All animals with
estrogen alone developed palpable kidney tumors at various intervals up to 10.5 to 11
months after start of the treatment. None of the animals that received testosterone and
none of the untreated animals had any kidney tumors.
Horning [95]: Primary kidney tumors were induced by implanting 20 mg pellets
of diethylstilbestrol subcutaneously, and 12 weeks later, a second one; 70 to 80% of the
male hamsters developed palpable renal lesions within 9 to 12 months following the
treatment with a single 20 mg pellet, and the incidence following introduction of the
second one was, in some instances, increased to 100%. These hamsters were 6 to 8 weeks
old. The most satisfactory way of obtaining successful transplantable renal tumors was
to graft them subcutaneously into host animals which had been pretreated with a 20 mg
tablet of stilbestrol three months prior to receipt of the tumor implant. In another series
of experiments, stilbestrol pellets and the tumors were grafted simultaneously into normal
hamsters which had not been previously treated with the synthetic hormone. The conclusions are that hormonal factors regulate the growth of transplanted and stilbestrolinduced tumors in the male hamster. The appearance and behavior of the dormant phase
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of grafted kidney tumors which exists in estrogenized host hamsters prior to the development of palpable lesions was described. Kidney tumors grafted subcutaneously into the
tails of pretreated hamsters metastasized more readily than those grafted into the subcutaneous tissues of the trunk. Comparison between the absorption rates of subcutaneously
implanted pellets of pure stilbestrol in the hamster, desert rat and albino rat shows that
the absorption rate of the hormone pellet is slower in the hamster than in the other two
species of rodents. There is extensive discussion here of the hormone dependence of
estrogen-induced kidney tumors and the relationship of the kidney to the sex hormone
system is questioned. Therefore, it cannot be assumed that all estrogen-induced kidney
tumors in the hamster will be necessarily endocrine-dependent lesions.
Horning [94]: Sixty-five hamsters, 6 to 7 weeks of age, of indeterminate ancestry,
underwent left nephrectomy prior to the implantation of 20 mg pellets of pure diethylstilbestrol in the region of the left flank. This was done 4 to 5 weeks after nephrectomy and,
in a group of 21 other hamsters, 10 to 12 weeks after nephrectomy. Controls were animals
left untreated after unilateral nephrectomy and animals which were of the same weight
as the treated nephrectomized ones which received only pellets of stilbestrol. The average
survival times ranged from 260 to 321 days. Nephrectomy accelerated the appearance of
renal carcinoma. The mean duration for tumor induction was 190 days in the nephrectomized series± 28.7 days, compared with 286 days± 23.5 days in the controls. It was also
noted that tumors arose quickly in the remnants of renal tissue accidentally left in situ.
Some of these tumors were grafted and grew only in estrogen-treated host hamsters.
There was a rather long period of latency. There is a discussion of the hormonal factors
essential to sustained growth of transplanted kidney tumors in the host hamsters.
Horning & Whittick [93]: This is a study on the histology of the kidney tumors induced
in 40 male golden hamsters by 20 mg pellets of pure diethylstilbestrol injected subcutaneouslyat 12 weeks of age. The microscopic and gross descriptions are very much as those of
other papers by KIRKMAN and his associates. Of interest are the associated estrogenic
changes in organs other than the kidney, which included pituitary tumors, adrenal adenomas and proliferative changes in the prostate glands, as well as changes in the epididymis,
seminal vesicles and testes. Twenty-eight of the 40 animals had hypophyseal tumors. In
one animal treated for 10 and a half months, the prostate showed squamous metaplasia and
keratinization in a focal distribution. The epididymis showed atrophic epithelium and
some squamous metaplasia and an increase in the fibromuscular stroma. There were no
tumors. In most instances, the testes were atrophic, and there was an inhibition of spermatogenesis; however, there was great variation. There were also variable changes in the
seminal vesicles.
Ising [99]: This study was designed to investigate the effect of one-sided ureterectomy on the development of kidney tumors in estrogen-treated male hamsters. Twelve
male hamsters were submitted to right ureterectomy and diethylstilbestrol powder was
made into 25 to 30 mg pellets which were implanted subcutaneously in the back of each
animal as controls. This was also done in 22 intact male hamsters and 6 female hamsters.
The animals were examined weekly and a large portion of the implants had been absorbed
in 200 to 250 days. In animals in which the whole implant had been absorbed, another one
of the same size was implanted. After 280 days of treatment, two of the ureterectomized
males had the first tumors, and all of the animals were then killed. In all 12 ureterectomized
hamsters there were large kidney tumors which always were larger on the ureterectomized
side. Of the intact animals, 12 had multiple renal tumors which were only pea sized.
Transplants of any of these tumors to untreated hamsters failed. It is concluded that
ureterectomy definitely increases the susceptibility of the kidney to estrogen-induced
kidney tumors. Whether this is due to a higher concentration of the carcinogen in the
ureterectomized kidney or to greater sensitivity of the damaged kidney to carcinogen is
not known. There were metastases in the abdominal wall. Again, no tumors were found
in females.
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The Syrian Golden Hamster in Chemical Carcinogenesis Research
HOMBURGER
Jones [100]: This is a preliminary paper on a limited number of tissue-culture studies,
using cell cultures of a stilbestrol-induced hamster kidney tumor as well as of normal
hamster kidney cells. When RNA preparations made from normal kidney and implanted
kidney tumors from the same animals were added to these cultures, after two days'
incubation in roller tubes considerable necrosis was seen when normal RNA was added
to the tumor cells. Conversely, when tumor RNA was added to normal cells, morphological changes occurred which made these cells resemble those of the tumor cultures.
However, these cultures were kept for only seven days. The experiments were inconclusive
even though the author states that in his opinion these results possibly represent an
example of aberrant morphogenesis which may be a more valid analog to malignancy
than transformation at the nuclear level which, to date, is far from proven. The conclusions
are not well supported by the data presented.
Kirkman [110]: This is a review article which deals with hamster tumors considered
as possibly resulting from direct hormonal action, namely, radiothyroidectomy-induced
tumors of the pituitary gland, estrogen-induced pituitary adenomas and renal carcinomas,
estrogen-androgen-induced leiomyomas of the uterus and vas deferens, and epitheliomas
of the flank organ and hair follicles. Also, it deals with hamster tumors produced
by indirect hormonal action such as adrenocortical adenomas following gonadectomy
and 37 different types of tumors having a higher incidence among about 3,000 hamsters
with known hormonal imbalances, and among about 1,200 hamsters with no known
imbalances.
Kirkman [106]: The fact that bilateral, multiple, malignant, renal neoplasms appear
in from 90 to 100% of male Syrian hamsters, implanted subcutaneously with 20 mg pellets
of diethylstilbestrol for 250 days or longer, is now well established. The tumors do not
appear in estrogenized females, except under conditions of low progesterone secretion,
e.g., in ovariectomized animals, in animals receiving diethylstilbestrol before puberty, or
between the middle of metestrum and proestrum, or in females whose anterior pituitary
glands have been 'masculinized' by an initial treatment with androgen during the first
few days of life. The failure of females to acquire renal tumors under conditions inducing
them in males is due, not to a sex difference in kidney tissue, but to environmental conditions. This is illustrated again in the following experiment.... Each of eleven 51-day-old
males received a diethylstilbestrol pellet plus one-third of a kidney from a newborn
hamster, subcutaneously; in five (Group 1) the donor was male; in six (Group 2) the
donor was female. Death occurred between ages of 263 and 425 days. Transplant growth
did not occur, but partial transplant survival was observed in four animals of Group 1 and
three animals of Group 2. In one hamster of each group clear-cut tumor tissue developed
from surviving kidney elements of the transplant. Of the eleven animals, primary tumors
occurred in all but two of Group 2. Metastases developed in one animal of Group 1;
however, this was not the animal showing tumor tissue in the transplanted kidney.
Kirkman [107]: This is a review of the induction, latent period, growth rate, prevention, regression, viability, transplantation and dependency versus autonomy of the estrogeninduced malignant metastasizing renal neoplasm in the Syrian hamster.
Kirkman [108]: This is a study on the continuous administration of estrogen to
Syrian hamsters which resulted in the appearance of malignant renal tumors in intact
males and gonadectomized males and females, but not in intact females. Administration of
progesterone with diethylstilbestrol prevented induction of renal tumors, and it was
suggested that the progesterone might be responsible for the failure of intact females to
acquire tumors. It was possible to induce kidney tumors in females by four methods:
1. starting treatment with estradiol and diethylstilbestrol during metestrum, 2. starting
treatment with diethylstilbestrol on the second, tenth or eighteenth day of life, 3. administering testosterone propionate on the first day and replacing it with diethylstilbestrol
on the fiftieth or 196th day of life, and 4. transplanting kidney tissue from newborn female
donors to diethylstilbestrol-treated male hosts. The following conclusions were made:
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It is possible to induce renal tumors by estrogen in female hamsters after removal of the
ovaries, at time of the progesterone secretion, before reproductive maturity and in
masculinized animals following treatment with testosterone propionate at birth; finally,
in females maintained in male environments.
Kirkman [103]: Treatment of male hamsters, or of gonadectomized hamsters of
either sex, with diethylstilbestrol continues to induce renal tumors as previously reported.
Such tumors have not developed in gonadectomized or non-gonadectomized males or
females receiving testosterone or progesterone together with stilbestrol. Growing,
subcutaneously implanted metastases have been recovered after 100 days in stilbestroltreated, spayed hosts, but not from non-gonadectomized, stilbestrol-treated male hosts.
Regression of tumors following cessation of treatment is known to occur in non-castrates,
but evidence on this point is still lacking for gonadectomized animals. Some tumor cells
are now known to arise from interstitial connective tissue near the cortico-medullary
border, but tumor cells of epithelial origin are believed to occur also. No spontaneous
renal tumors of any type have been observed. There is evidence suggesting pituitary
gland involvement in the induction of renal tumors. Data are based upon more than 450
animals sacrificed. Experiments are now in progress designed to complete the testing of
the hypothesis that in the male hamster, but not in the female, stilbestrol tends to block
LH secretion as it does ACTH secretion. Since either testosterone or progesterone prevents the induction of renal tumors by stilbestrol such a sex difference in the response of
the anterior pituitary gland to stilbestrol would explain the sex difference in the induction
of renal tumors.
See Kirkman [109], p. 176.
Kirkman [106a]: Twenty-two male hamsters were divided into two groups of equal
size. The right kidneys of four animals in each group were deeply punctured by a 16-gauge
B-D needle, the remaining fourteen by a 13-gauge needle. A 20-mg pellet of diethylstilbestrol was implanted subcutaneously in each animal of one group, the other group
serving as a control. Animals were sacrificed after 200 days of treatment, at an age of
250 days. In the diethylstilbestrol-treated group small foci of tumor cells were found in
association with the puncture scar in all animals; in three of the eleven hamsters no other
tumor foci were found in the right kidney, and in one no tumors were found in the left
kidney; in one animal the only tumors found in either kidney were in association with the
puncture scar. No tumors occurred in either kidney of any of the eleven control hamsters .
... It is concluded that in diethylstilbestrol-treated hamsters mechanical traumatization of
renal cortical tissue predisposes it to neoplastic transformation.
See Kirkmann [105], p. 175.
Kirkman & Bacon [116]: This is a paper on studies in 131 male hamsters treated
with diethylstilbestrol for various periods of time ranging from 50 to 600 days. The
number of animals showing renal tumors was approximately 100 (about 80% of the
animals). Of these, half had metastases. Estradiol and diethylstilbestrol were found to be
equally effective. The first renal tumors found were in hamsters receiving subcutaneous
injections of 0.6 mg of estrogen in 0.4 cc sesame oil every other day, starting at the 35th
to 77th day of life and continuing from 107 to 210 days. Injections were then continued
with 0.6 mg suspended in 0.2cc of 0.9 sodium chloride until death, or an additional 215 to
360 days. This was done with hamsters from various sources and predominantly from
the author's own closed colony. These were not inbred. There were no tumors in 45
untreated male hamsters, nor were there any kidney tumors in the twelve animals treated
for less than 150 days. The summary states that in intact male golden hamsters treated
continuously with diethylstilbestrol, no renal tumors developed in less than 150 days of
treatment. There were tumors in one animal treated for 180 days and in ten animals treated
for 150 to 190 days. Metastases were not found outside the abdominal cavity. All of
eighteen castrated animals treated similarly with stilbestrol from 248 to 415 days developed
renal tumors. Seventeen per cent of these metastasized.
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Kirkman & Bacon [117]: The minimum effective dose of stilbestrol for the induction
of renal tumors in the golden hamster lies between 0.03 and 0.09 mg per day. While 0.6 mg
is effective when injected every second day, it is not effective when it is administered
every tenth day. Over a period of 400 days, this would represent a total of only 24 mg of
stilbestrol, or one-fifth of the known effective dose. One-half of that, i.e. 12 mg given as
0.06 mg every second day, is equally ineffective. Failure of 0.6 mg given every tenth day
may be due, not to discontinuity in absorption, but to inadequate total amount administered. The smallest amount of stilbestrol found effective in injected animals was 54 mg,
0.6 mg every second day for 180 days in an intact male or in animals treated with implanted
pellets between 16 and 17 mg given over 270 days. The age of the male at the beginning
of the treatment appears to be unimportant. Metastases limited to the abdominal cavity
were common in all tumor-bearing animals. Absolute and relative kidney weights were
greater for all renal tumor-bearing animals than for treated or untreated non-tumorbearing animals.
Kirkman & Bacon [115]: This appears to be the first detailed report by KIRKMAN
et af. [see also, 133] on renal tumors induced by chronic treatment with diethylstilbestrol
in male hamsters. There were observations on nine animals which had been treated for
from 215 to 360 days with diethylstilbestrol in physiological saline given every second
day, and also with stilbestrol in sesame oil. The total treatment ranged from 217 to 497
days. This included animals treated with subcutaneous pellets. There were about 20
animals with tumors, of which 8 showed metastases. The total number of animals is not
easy to derive from the tabulations in this paper. The statement is made that renal tumors
appear in all males treated with estrogens for 250 days or longer, except in those in which
diethylstilbestrol cholesterol pellets were implanted. In these, no renal tumors were
detected and no renal tumors were observed in any female, in any untreated male, in any
treated castrated male, or in any control treated with sesame oil or with saline solution.
Tumors were always bilateral and adenomatous in character and located within the cortical
area of the kidney.
Kirkman & Bacon [114]: Of twelve male hamsters, injected subcutaneously on
alternate days with 0.6 mg of diethylstilbestrol, in the form of microcrystals suspended in
saline solution, for from 320 to 496 days, bilateral, sudanophilic, renal adenomas occurred
in 7 and adenocarcinomas in 5 individuals. Ten males treated for 90 to 160 days developed
no renal tumors; neither did 14 comparably treated females, 25 untreated females nor 30
untreated males. The tumors appear to arise from a narrow band of sudanophilic epithelial
cells near the renal pelvic rim. A similar band occurs in females. From this band, in treated
males only, cords bud outward into the adjacent renal cortex. Different tumor masses are
well defined but not encapsulated, vary greatly in size and spread by contact and invasion.
Eventually separate metastases may occur from diaphragm to scrotum. The tumors
consist primarily of intricate masses of branching, anastomosing cords varying from one
to 20 or more cuboidal cells in width and surrounded by blood capillaries and a very
delicate network of reticular and collagenous fibers. Many mitoses occur. Adenomas
may contain large necrotic areas, or large cavities filled with clear, non-sudanophilic fluid.
Within cords there are few free surfaces. More or less necrotic cells stain intravitally with
trypan blue and frequently contain many hyaline droplets characteristic of so-called
'colloid degeneration'. Metastases retain the architecture of the primary tumor.
Kirkman & Robbins [121]: This is a description of histological findings in the renal
carcinoma induced by estrogen in the Syrian hamster. The histogenic conclusion from
these studies was that most cells arise from tubular epithelium and that the proximal
convolution is definitely involved, but that probably tumors arise from distal tubules
also. There was a problem in histological classification of these tumors.
Kirkman & Robbins [119]: As reported elsewhere the administration of estrogens,
under certain conditions, is followed by the appearance of tumors resembling embryomas
in hamster kidneys .... The majority of tumor cells owe their origin to connective tissue
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Kirkman & Wurster [123]: Malignant renal neoplasms in estrogen-treated male
hamsters are established. Females have not developed them; this failure is attributed to
circulating progesterone. Conditions of treatment: starting age, 50 days; duration, 250
days or longer; autopsy age, 300 days or older; estrogen, 20-mg pellets of diethylstilbestrol
or estradiol, subcutaneously.... Results were as follows: la. no tumors in any of 37
untreated males; lb. tumors in 56 of 57 stilbestrol-treated males; lc. tumors in all of 14
estradiol-treated males; 2a.no tumors in any of76 untreated females; 2b.no tumors in any
of 53 stilbestrol-treated females; started at undetermined stages of the estrous cycle;
2c. no tumours in any of 11 stilbestrol-progesterone-treated males .... If progesterone is
responsible for failure of tumors in stilbestrol-treated females, it might be possible to
induce tumors under the following conditions: a) after ovariectomy, b) during preadolescence, c) during late metestrum, and d) in postadolescent females, whose pituitaries have
been 'masculinized' at birth by androgen. Tumors occurred: a) in fourteen of 27 stilbestroltreated; in ten of sixteen estradiol-treated, spayed; but in none of twelve untreated,
spayed hamsters, b) in three of ten females receiving stilbestrol from 18th day of life; in
three of five started on 10th day; and in three of three started on 2nd day, c) in one of
five started during late metestrum, d) in one of one 'masculinized' female .... Thus, under
chronic stilbestrol-treatment, progesterone secretion prevented induction of renal tumors
in female hamsters. Tumors may be induced by combining estrogen treatment with low
progesterone secretion.
Manning et of. [131]: This is a review article on the estrogen-induced kidney tumor;
it covers the original literature on gross anatomy, histology, histochemistry, electron
microscopy, classification, latent period, metastases, mechanism for tumor induction or
non-induction, regression, transplantation, autonomy, biochemistry and antigenic aspects;
this section is followed by an extensive study of the relation of p-glucuronidase in the
kidney and the liver to tumor formation by estrogen. There were four groups of animalscontrols, castrates, diethylstilbestrol-treated and castrated, and diethylstilbestrol-treated.
The total number of animals was 70 prepuberal and 48 postpuberal golden hamsters.
Doses of stilbestrol were 40 mg in two 20 mg pellets. Implantation and/or castration was
carried out under Nembutal anesthesia and pellet weights as well as animal weights were
recorded at the start of the investigation and daily thereafter. Prepuberal animals were
killed at 15, 30, 60, 90 and 150 days; postpuberal animals were killed at 30, 90 and 150
days following the commencement of the experiment. Biochemical and histochemical
procedures for p-glucuronidase were those reported in the literature. The summary of the
observations is as follows: Histochemically, there were two areas of glucuronidase,
marked activity in zone 1 and no activity or very little activity in zone 2. Estrogen and
castration independently demonstrated no significant change in the quantity of p-glucuronidase activity in the kidney and liver, while the combined treatment had an appreciable
effect on enzyme activity. Evidence is presented which relates the action of estrogen to
releasing enzymes contained inside the plasmic particles, such as mitochondria or endo-
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hyperplasia. Since the cells contain sudanophilic lipoids and alkaline phosphatase, they
are readily identified. As hyperplastic areas enlarge, growth pressures frequently result
in collapse of portions of adjacent tubules, forming two layered cups partially enclosing
hyperplastic areas. The outermost layer involutes leaving a crescent or demilune of simple
cuboidal epithelium, the concave surface of which represents the original vascular poles.
The original apical poles become vascularized and cell nuclei reverse their polarity. Within
the cytoplasm of occasional cells, a small vacuole appears surrounded by basal bodies,
presumably of centriolar origin; from these cilia extend. In the great majority of 'crescents'
examined the cells have already acquired fully formed ciliated borders, always directed
centrally from former vascular poles, now facing central tumor nodules. Cells of epithelial
origin have more acidophilic cytoplasm and more deeply staining nuclei than do cells of
connective tissue origin. The crescents, or pseudo-glomeruli, are as conspicuous in extrarenal metastases as in renal tumors, and must, therefore, be self-perpetuating.
HOMBURGER
plasmic reticulum. There were other observations which are not particularly pertinent to
this review.
Mannweiler & Bernhard [132]: In summary, this study is concerned with the
electronmicroscopic examination of 6 kidney tumors of male golden hamsters induced by
estrogen. The control kidneys were those of 6 adult hamsters of both sexes and 7 newborn
hamsters. The tumor cells demonstrated structural dedifferentiation in various degrees
and necrobiotic phenomena. In addition, a highly differentiated ciliated border was formed
in the tumor cells which has been observed in neither kidneys of the control hamsters
nor in other mammals. The ultrastructure of the cilium is identical with that of protozoa
and of ciliated epithelial cells in different species.
Matthews et al. [133]: The kidneys of golden hamsters treated for long periods with
diethylstilbestrol and sesame oil tend to undergo marked changes of a destructive character.
In the male, these changes are primarily in the direction of potentially malignant tumor
formation. In the female, they are in the direction of glomerulonephritis. Kidney changes
were observed in all of the 9 treated animals. Of these changes, by far the most conspicuous
were adenomas found in each of the 6 males. In size, these tumors ranged from small
nodules of a few cells to masses of about one-third the volume of the control kidney.
McGregor et al. [134]: Male golden hamsters were treated with diethylstilbestrol
to produce renal tumors. Analysis of total fat, protein, carbohydrate and nucleic acid
levels in both kidney and liver was made during the early stages (3 months), as tumors
became detectable microscopically (8 months), and when tumors were well established.
Regressions were following during 10 months after withdrawal of the diethylstilbestrol
for one month; regression was complete in only 60% of the animals. There were no
significant changes in the parameters studied until the tumors were fully developed. No
changes in renal function were found during 8 months of diethylstilbestrol treatment.
Muhlbock [148]: This is a general review of estrogen- and testosterone-induced
tumors in various species, with special emphasis on breast cancer of mice, listing kidney
and epididymis tumors in hamsters. In the discussion, there is a brief reference to carcinogenicity of testosterone for the flank organ.
Noble [151]: This is an extensive review on hormonal regulation of tumor growth
to which one may refer; however, it is not especially directed toward problems of carcinogenesis in hamsters.
See Paschkis et al. [153], p. 201.
Pol'kina [156]: Twenty-four animals, cricetus aura/us (15 male and 9 female), were
experimented upon. Kidney tumours developed in 9 male animals that had been given
180 mg and more of diethylstilbestrol and had survived for more than 250 days. According
to their histological structure they were adenomas, papillary cystoadenomas or adenocarcinomas. They appeared out of epithelial elements of the cortical layer of the kidney
and possessed infiltrative growth, growing sometimes into the blood vessels and muscular
wall of the ureter. These tumours can metastasize to the spleen, for instance.
Pol'kina [157]: This is essentially a confirmation of KIRKMAN'S work. Three groups
of hamsters were used. Group 1: 49 males received 20 to 120 mg of sinestrol over 5 to 216
days and 18 females received 20 to 100 mg of sinestrol over 5 to 178 days. Nine of these
females were castrated a week before estrogen was given. Group 2: 30 males received
20 to 280 mg of diethylstilbestrol over 10 to 410 days and 10 females received 60 to 180 mg
of diethylstilbestrol over 65 to 357 days. Group 3: 8 males received 80 mg of sinestrol and
60 mg of diethylstilbestrol and survived 244 to 330 days. The one female which was
included received 40 mg sinestrol and 60 mg diethylstilbestrol and survived 195 days.
Administration was by subcutaneous pellets containing paraffin and lanolin as binders.
These were implanted under the skin once a month. The conclusions are that the administration of sinestrol and diethylstilbestrol to male and castrated female hamsters caused
focal proliferation of the epithelium of the main tubules and glomerular capsule with
kidney tumors which developed eventually into adenomas, papillary cysts, and adeno-
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carcinomas capable of metastases. Kidney tumors develop in about 90% of the animals,
but only in males or castrated females, and not in the intact female.
Riviere et at. [172]: Twenty male hamsters, 8 to 10 weeks old, received subcutaneous
implantation of 25 mg diethylstilbestrol dipropionate and 100 mg acetate of desoxycorticosterone; six months later, a new implantation of the same hormone was made. Fifteen
months after the beginning of the treatment the animals died and the kidney was examined
histologically. No tumors were found in the control animals and no tumors were found in
the animals having received desoxycorticosterone alone or estrogen and desoxycorticosterone. It is concluded that desoxycorticosterone in the hamster is an antagonist to the
carcinogenic renotropic effect of estrogen.
Riviere et al. [180]: This is a review of hormone-induced tumors in the hamster
starting with the estrogen-induced kidney tumor and discussing the leiomyomas of the
uterus and epididymis which are caused by estrogen and androgen combinations. It is
noted that so far no tumors of the breast have been induced by hormones in the hamster,
whereas they can be produced by methylcholanthrene feeding. It is noted that most
hormone-induced tumors in the hamster are hormone-dependent upon transplantation.
Hormone antagonisms, such as inhibition of kidney cancer induction by progesterone and
desoxycorticosterone, are discussed. The flank organ of the hamster, which is also susceptible to tumor induction by the combination of estrogen and androgen, is not mentioned
in this review.
See Sajjiotti et al. [193], p. 201.
See Tomatis [224], p. 202.
Ward et al. [228]: KIRKMAN has shown that progesterone secretion in the female
hamster is important in determining susceptibility of the kidney to tumor production
by estrogens [107]. The suggestion was made that since estrogen enhances luteinizing
hormone action, if corpora lutea arc present progesterone secretion is augmented. The
present studies are preliminary to more detailed studies of this question. It was first
determined whether luteinizing hormone (LH) could be detected in the pituitary of the
male during prolonged estrogen (diethylstilbestrol, DES) administration, since the male
pituitary is uncomplicated by cyclic variations and more experience is available with
tumorigenesis in males .... Pituitaries from male hamsters after 0, 3, 6, 7 or 12 months
treatment with DES were collected at autopsy. Pituitaries were weighed, dried in cold
acetone, and stored in the freezer until assay. LH content was estimated on saline extracts
of the homogenized pituitaries using the Parlow ovarian ascorbic acid depletion assay;
a unit = t [Lg NIH-LH-S-1. Adult male hamsters averaged 5.2 units per pituitary. This
decreased to 1.3 units after 3 months, and after 6 to 12 months LH per pituitary averaged
0.74 units and was essentially constant, within 95% confidence limits for the assay.
Ward et al. [229]: This is a study of the effect of packing of the diethylstilbestrol
pellets on the rate of absorption of stilbestrol. Three different types of pellets were used,
the absorption rates varying from 150 to 630y of diethylstilbestrol per day for the different
types. In each case there was a higher absorption rate during the first week. Tissue distribution of stilbestrol was measured by means of 04-labeled diethylstilbestrol pellets. Tumor
production by the three types of pellets was studied in a limited number of hamsters for
a period of 6 to 8 months. All three types of pellets produced kidney tumors, provided
the stilbestrol was continuously present, the rate of absorption being an important
consideration in experimental design to assure the latter requirement. In addition, atrophy
of the testicle was found to be a reliable indicator of the constant presence of estrogen.
Weiler [230]: This paper deals with the antigenic differences between stilbestrolinduced kidney carcinoma of the golden hamster and the normal kidney. Cytoplasmic
fractions prepared from both normal kidney and from the estrogen-induced tumor were
tested against rabbit anti-kidney and anti-tumor antigens. The antigenic relationship
between microsomes and mitochondria from normal hamster kidney and from stilbestrolinduced kidney carcinoma have been investigated. When tumor antisera were exhaustively
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absorbed with kidney particles, there remained a weak activity toward the homologous
antigen. Tumor particles therefore seem to contain a small antigenic component which
is not present in normal kidney, but which can be found in the other organs of the hamster.
With unabsorbed antisera, quantitative differences were detected between cytoplasmic
particles from normal and malignant tissue when cross reactions with the respective
heterologous antisera were carried out. The antigenic differences between normal and
malignant tissue, as reported in the present paper, were very similar to those found
previously in liver carcinogenesis.
Weiler [231]: This author had previously observed the qualitative differences between
cytoplasmic particles from normal hamster kidney and from kidney carcinoma. This was
analogous to similar observations made for normal liver and azo-dye-induced liver carcinoma. Using fluorescent methods, it was found that fluorescent kidney-specific antibodies
gave no staining reaction with tumor cells and this is in accordance with the preceding
publication by the same author [230], where no kidney-specific antigen could be found in
tumor tissue.
Male Genital Tract
1. Testes. No tumors have been produced in the testes.
2. Prostate. Proliferative changes, metaplasia and keratinization
have been noted in the prostates of estrogen-treated hamsters, but
no true carcinomas have been induced.
3. Epidit!Jmis. Hormone-dependent transplantable leiomyomas
have been caused in hamsters by prolonged combined treatment with
estrogens and androgens. There were changes in the pituitary of these
animals, but hypophysectomy failed to prevent such tumors. Cell
cultures were no longer hormone-dependent, but organ cultures
remained dependent on androgens and estrogens.
1. Uterus. Estrogen treatment caused cystic hyperplasia and leiomyomas in the uteri of hamsters. Progesterone prevented the cystic
hyperplasia. While some of these changes (cystic hyperplasia) are
analogous to precancerous lesions in women, no endometrial carcinoma has been produced in hamsters by estrogens.
Leiomyomas of the uterus were also found in hamsters treated
simultaneously with estrogens and androgens. Some of these were
transplantable, growing in estrogen- and androgen-treated hamsters.
In isolated studies, testosterone alone seems to have caused at least
one papillary adenoma of the uterus.
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Algard [5]: In vitro study of an androgen-estrogen-induced dependent leiomyosarcoma of the epididymis in the Syrian hamster showed that hormone dependency is not
reflected in cell culture. In organotypic culture, however, this tumor failed abruptly and
completely unless the two sex hormones were incorporated in culture medium. These
findings are interpreted to suggest that hormone dependency is a tissue phenomenon
divorced from the economy of the whole animal.
Bacon [10]: In a study of the induction of renal tumors in male hamsters by diethylstilbestrol, 20 mg pellets of the estrogen were implanted subcutaneously between the
scapulae in one series (Group 1) while a second group received similar pellets, but of
diethylstilbestrol and cholesterol in a ratio of 1 : 4 (Group II). The periods of treatment
ranged from 92 to 360 days. At autopsy the animals ranged in age from 145 to 413 days.
In view of the seasonal changes in the testes, 14 untreated males, sacrificed at various
times during the year, were employed as controls. . .. The average weight of the left
testis in 18 animals of Group I was 77.5 mg, with a range of 55.3 to 112 mg. The average
weight of the left testis in 15 animals of Group II was 786.5 mg. The corresponding average
in controls was 1,054 mg, with a range from 280 mg (January) to 1,863 mg (May). Thus,
the response of the hamster testis to diethylstilbestrol does not support the suggestion of
other workers that the effective dose of sex hormones is reduced by administration in
cholesterol pellets.
Bacon [11]: As part of an investigation of endocrine factors in the production and
control of renal rumors in hamsters, a group of 10 females was treated with stilbestrol and
testosterone. Beginning on the 50th day of life each animal received 0.6 mg of stilbestrol
and 1.0 mg of testosterone base in saline suspension every other day. After from 82 to 89
days of treatment, injections were discontinued and each animal was implanted subcutaneously with a 20 mg pellet of stilbestrol and a 30 mg pellet of testosterone propionate.
The animals died or were sacrificed from 223 to 400 days after treatment was started. In
addition to the cystic glandular hyperplasia encountered in all uteri, multiple leiomyomas
in one or both uterine horns were found in 6 of the 10 animals. The tumors were positive
to tests for alkaline phosphatase but negative to those for acid phosphatase and lipase. Of
20 females treated for equal or greater lengths of time with stilbestrol alone, first in oil and
later in saline suspension, a single tumor nodule developed in the uterus of each of two
animals. These were leiomyomas, but presented a somewhat different histological picture.
No uterine tumors have been found in any untreated females in the author's colony....
Thus the hamster differs from other species in which testosterone has been reported to
prevent the development of uterine tumors.
Bacon [12]: In connection with an investigation of the endocrine factors involved
in the production and control of renal tumors in hamsters, ten females and eleven males
received diethylstilbestrol and testosterone propionate simultaneously from pellets
implanted subcutaneously on the fiftieth day of life. The animals died or were sacrificed
after from 223 to 543 days of treatment. Cystic glandular hyperplasia was found in the
uteri of all females and extensive hyperplasia of muscle, connective tissue and epithelium
throughout the reproductive tract of the males. In addition, multiple leiomyomas were
found in one or both uterine horns of six of the ten females and leiomyomas of one or both
epididymides in five of the eleven males. The tumors from the two sexes were histologically
indistinguishable. Among twenty females and sixty males treated for equal or greater
lengths of time with diethylstilbestrol alone, a single tumor nodule developed in the
uterus of each of two females and none in any of the males. No tumors of the uterus or of
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2. Uterine cervix. Cervical cancers have been produced by painting
with BP and with DMBA in acetone. Painting with tobacco tars
caused no tumors. Pellets of estrogen inserted into the vagina caused
some cervical carcinomas.
HaMBURGER
the epididymis have been found in any untreated animals in the author's colony .... These
tumors appear to be of the same type as those which, in the guinea pig, may be produced
by treatment with estrogen and prevented by simultaneous administration of testosterone.
Bacon [13] : A group of 11 male hamsters received diethylstilbestrol and testosterone
propionate simultaneously from subcutaneously implanted pellets. The pellets were
implanted on the fifthieth day of life, the period of treatment ranged from 271 to 543 days,
and the age at autopsy from 321 to 593 days. All of the animals showed extensive hyperplasia of muscle, connective tissue and epithelium throughout the reproductive tract
comparable, with few exceptions, to that previously reported following treatment with
diethylstilbestrol alone. In addition,S animals showed leiomyomas of one or both epididymides, some of considerable size. In the longest treated animal the tumorous left epididymis
weighed 6,626 mg. No such tumors have been found in 13 males treated simultaneously
with diethylstilbestrol, testosterone propionate and progesterone for equal or greater
lengths of time, nor in more than 60 males treated with diethylstilbestrol alone for equal
or greater lengths of time, nor in any untreated controls. Treatment of a group of males
with testosterone propionate alone has been started, but the animals have not yet come to
autopsy. These tumors are histologically indistinguishable from those previously reported
in the uterus following administration of diethylstilbestrol and testosterone propionate
to female hamsters.
Bacon & Kirkman [14]: In conjunction with an investigation of renal tumors induced
by diethylstilbestrol in hamsters, the changes in the reproductive tracts of 15 treated
males and 11 treated females and 18 controls were studied. The average animal received
0.3 mg of the estrogen per day for a period of 318 days. The period of treatment ranged
from 90 to 496 days .... The female tract showed reduction in size of ovaries, decrease in
size and number of ovarian interstitial cells, absence of normal follicles older than the
stage of beginning formation of the antrum, and absence of corpora lutea. Cystic hyperplasia and gland formation were found in the oviducts. The uteri showed extensive cystic
hyperplasia except in two cases where large fibroids occurred. The endometrial stroma
was heavily infiltrated with plasma cells, and multinucleated giant cells were present in
some cases. Cervical hyperplasia with squamous metaplasia and cornification of surface and
glandular epithelium occurred, and the vagina showed cornification throughout its
length .... In males progressive reduction of the spermatogenic epithelium was observed
with ultimate transformation to simple epithelium. Reduction in number and, in some
cases, almost complete disappearance of interstitial cells occurred. The duct system was
either small and atrophic throughout or occasionally cystic. Some squamous metaplasia
with keratinization was found in the prostate near its junction with the epithelium of the
urethra.
Chu el at. [35]: The uterine cervices of twenty animals were painted with DMBA;
those of 30, with BP; those of 30, with tobacco tar; those of 20, with acetone, and the
cervices of 6 were sham painted. This was done biweekly with a test solution of 1 %
DMBA or BP in acetone or 50% crude tobacco tar in acetone. After 100 paintings over a
period of appoximately 12 months, no cancers had been produced by the crude tobacco
tar. There were 54% cervical cancers in BP-treated animals and 100% in DMBA-treated
animals. There was a loss of cyclic pattern in the vaginal smears of all animals that had
cervical inflammation, including the acetone-treated ones, which did not develop cancer.
See Della PorIa [41], p. 196.
Donlenwill el at. [58]: This paper contrasts the negative result of subcutaneous and
chronic estrogen administration with the production of cervical carcinoma by local
insertion into the vagina of estrogenic preparations. Thirty female hamsters of unstated age
received for one and a half years, every 2 days, 0.6 mg of diethyldioxystilbain dipropionate
(Bayer) in oil subcutaneously. At the end of this period, histological studies were made,
including serial sections of the cervix and vagina. In the second experiment, thirty female
hamsters received, after the age of 6 weeks, every eight weeks, pellets made from the
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powder of the same preparation, which were inserted into the upper portion of the
vagina. Ethyl acetate served as a binder. These pellets measured 2.5 mm in thickness and
8 mm in length, and contained 40 mg of the estrogen and Y2 mg of the carrier. After
insertion of the pellet under anesthesia, the vagina was closed by means of a surgical clip.
Rarely were there remnants of the pellets at the end of eight weeks. Duration of the
experiment was 10 to 12 months. Sacrifice was at 14 to 16 months, and serial sections of
the cervix were made. In none of the subcutaneously treated animals were there any
vaginal or cervical carcinomas. Following the insertion of pellets into the vagina of nine
animals which survived for 14 months, there were 6 cancers of the vagina and cervix.
In three additional animals, there were atypical epithelial proliferations of the cervix
and vaginal mucosa. It is argued that the estrogen per se was not carcinogenic, but required,
in addition, mechanical irritation by the local pellets.
Kirkman [102]: Seven tumor types were found in 302 hamsters; two, and possibly
four, types were induced by diethylstilbestrol. Twenty-eight of 65 diethylstilbestroltreated males developed renal mixed tumors; two had received head X-ray treatment
also. The 28 included all but one treated for 250 days or longer; six showed metastases.
Five of the 28 possessed renal capsular leiomyomas also, as did one of seven diethylstilbestrol-treated castrated animals. Two of 29 diethylstilbestrol-treated females developed
uterine leiomyomas. Of six X-rayed males one acquired a rhabdomyosarcoma. Nineteen
of 65 males and 10 of 29 females treated with diethylstilbestrol showed an increase of 100%
or more over the mean pituitary weight: body weight ratio of 40 untreated controls,
suggestive of pituitary adenomas. Similar increases were found in 6 of 8 gonadectomized,
stilbestrol-treated animals; in all of seven X-rayed, stilbestrol-treated females; in two of
21 males given stilbestrol plus cholesterol (1 :4); and in one of 7 females given stilbestrol
plus testosterone. Thirteen adrenal adenomas occurred (2 of 56 animals receiving ZnCI
in right testes; 1 of 64 stilbestrol-treated males; 1 of 20 stilbestrol:cholesterol-treated
males; 1 of 25 untreated males; 3 of 26 untreated females; 2 of 8 sesame oil-treated females;
2 of 5 X-rayed males; and 1 of 3 X-rayed females). One hepatoma occurred in an untreated
male.
Kirkman & Atgard [112]: Hormone-dependent leiomyosarcomas of the ductus
deferens epididymal tail complex appeared in virtually 100% of Syrian hamsters treated
simultaneously with androgens and estrogens for approximately 400 days. Hypophysectomy did not prevent tumor induction and upon transplantation, these tumors did not
change in respect to hormone dependency. Neither hormone alone supports growth.
This tumor was induced in 227 animals which received subpannicular pellets yielding a
mean daily absorption of 0.11 mg for diethylstilbestrol and 0.15 mg for testosterone
propionate. After an induction period of 200 to 300 days, this treatment was interrupted
and regression occurred. If only one of the hormones was withdrawn after 400 days, the
other would support tumor growth for about 200 additional days and subsequent transplantations of such tumor tissue into androgen-estrogen-treated hosts resulted in renewed
tumor growth. With increased transfers (as many as 60) into androgen-estrogen-treated
animals, the latent period was reduced to about 40 days. The transplanted tumors metastasized. [See also 105].
Kirkman & Bacon [118]: Bilateral, multiple, benign leiomyofibromas appear in the
uterine horns and in the deferent ducts of Syrian hamsters which have been implanted
subcutaneously with pellets containing both diethylstilbestrol and testosterone propionate
for 350 days or longer; they may appear after 100 days. Progesterone prevents neither
induction nor growth of the tumors, which are transplantable in intact, or gonadectomized,
males or females, as estrogen-androgen-dependent tumors.... Latent periods were
shortened from 100 to 20 days between the first and fifteenth transfer of the uterine tumor,
and from 100 to 35 days between the first and eleventh transfer of the vas deferens tumor.
The uterine tumor was autonomous by the tenth transfer. The mean growth rates of the
uterine tumor increased from 56 mg/day in males, or 260 mg/day in females, for the first
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HOMBURGER
transfer, to 1500 mg/day for the fifteenth transfer in males, or 1950 mg/day for the tenth
transfer in females. Vas deferens tumor growth rates increased from 5 mg/day for the first
and second transfers in males and females to 630 mg/day for the eleventh transfer in males,
and 790 mg/day for the seventh transfer in females .... The first transfer of the uterine
tumor did not grow but remained histologically healthy during 597 days in untreated
females. No remnants of the second transfer of the vas deferens tumor, after 484 days in
untreated males, or after 347 days in untreated females, were observed; nor were there
remnants of the second transfer of the uterine tumor, after 398 days of testosterone
propionate in females. There was slight growth-25 mg in males and 395 mg in females,
following 212 days of treatment with diethylstilbestrol. No remnants of fourth transfer,
vas deferens tumor, after 150 days, were noted in females receiving testosterone propionate
or diethylstilbestroL ... The first transfer, vas deferens tumor, was dormant for 200 days
in untreated males, and attained a weight of 1896 mg during 300 days of subsequent
treatment with diethylstilbestrol and testosterone propionate.
Kirkman & Robbins [120]: Of 2,452 hamsters autopsied in this laboratory, 64 (20
males, 15 females, 15 castrates and 14 ovariectomized) were implanted subcutaneously
with pellets of testosterone propionate alone. A single example of each of seven different
types of tumors occurred only among these 64 animals. Four additional tumors (one
thyroid adenoma, one pancreatic islet adenoma, two flank organ tumors) and 35 adrenal
cortical adenomas found in this group were encountered also in hamsters treated otherwise
and all of these, except the islet adenoma, occurred spontaneously, too .... Of the seven
tumors the following five were malignant: adrenal cortical carcinoma, pancreatic carcinoma, malignant hepatoma, dermal sarcoma, and a tumor of uncertain classification. Two
were benign: a thecoma and a hard fibroma behind the right eye .... Of the animals
bearing the seven tumors, the youngest was 608 days old; 58 of the androgen-treated
animals ranged from 608 to 950 days in age .... Among 191 normal, untreated hamsters
only four types of tumors were encountered; the youngest tumor-bearing animal was
200 days old; 139 of the animals ranged from 200 to 985 days in age ... , In conclusion, it
is suggested that testosterone propionate may act as a nonspecific carcinogen in the Syrian
hamster.
See Paschkis et al. [153], p. 201.
Rakoff et al. [164]: Continued administration of estradiol to oophorectomized adult
golden hamsters caused a marked 'cystic' hyperplasia of the endometrium, characterized
by the presence of numerous large dilated tubular glands lined with low epithelium and
surrounded by small closely packed stromal cells. This pattern appeared quite regularly
within four weeks with the subcutaneous injection of an aqueous suspension of estradiol
crystals, 100 micrograms once weekly, and within two or three weeks when the dose was
200 micrograms weekly. These changes were preceded by simple hyperplasia, evidenced
by smaller glands lined by tall columnar epithelium, with piling up of cells and numerous
mitoses. Almost complete regression occurred within four weeks after discontinuation
of injections, but more rapidly if progesterone was given (3 mg in aqueous suspension).
The simultaneous administration of 10 mg of an aqueous suspension of crystalline
progesterone with each injection of estradiol almost completely prevented the hyperplastic endometrial changes but produced a marked decidual-like reaction of the stroma
and sometimes the appearance of an exudate containing round cells. Similar findings were
noted after more prolonged administration of both hormones (total of 1000 y of estradiol
and 100 mg of progesterone in ten weeks).
Reynolds & Turner [171]: The Me-induced sarcoma of Lutz has been found very
satisfactory for the study of glycolysis and also for the testing of compounds considered
possible for inhibiting tumor growth. For these purposes the Lutz tumor compares
favorably with the familiar Walker rat carcinosarcoma 256. This paper presents evidence
to support this contention .... When the hamster sarcoma was carried in the subcutaneous
tissue of the back, optimum growth was reached in 3-4 weeks after transplantation. The
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rate was 89% in 6-10-week hamsters of either sex. The take rate for the Walker tumor was
95%. After 125 transplants the histological appearance of the hamster sarcoma was
essentially that of the original induced tumor. The tumor was composed of large spindle
cells with abundant cytoplasm and irregular nuclear structures. It suggested a fibrosarcoma
of considerable growth activity, as shown by the numerous mitoses and cytologic anaplasia.
There was very little tumor necrosis. ... Some metabolic activities of the two tumors
were compared. When water homogenates of both tumors were assayed for phosphohexose isomerase and for lactic dehydrogenase content, these enzyme activities were found
to be similar. Anaerobic glycolysis was also measured manometrically in water homogenates incubated in a medium containing phosphate buffer, bicarbonate, ATP, DPN,
Mg+, pyruvate, and KF. The amount of CO2 evolved from the buffer by acid production
was about the same for the two tumors. Thus, the glycolytic activities studied showed
practically identical values, as based on wet weights.
Riviere et al. [176]: In hamsters, the subcutaneous injection of 20 mg of MC or BP
causes, in all cases, tumors. One of the MC-induced tumors was transplanted in 13 successive passages during 18 months. Takes were 100%. This tumor histologically is a
polymorphosarcoma and metastasizes to lungs, lymph nodes and sometimes kidneys.
Riviere et al. [179]: This paper contains interesting speculations regarding the
tendency of hamster tumor to metastasize. Three hundred twenty-four golden hamsters
received a single subcutaneous injection of carcinogenic substances-MC, BP and DMBA.
One hundred ninety sarcomas developed, often metastasizing, as follows: 118 lung
metastases, 30 lymph node metastases. The following conclusions were drawn: 1. The
ratio of the tumors obtained is a function of the dose. 2. The average survival of the animal,
on the contrary, decreases for higher doses. 3. The influence of dose on the occurrence
of the metastases is significant. Hamsters are the material of choice for the study of problems concerning metastatic processes in chemically induced tumors.
Riviere et al. [174]: Pellets of 100 mg of testosterone propionate were given subcutaneously to 20 male and 20 female hamsters aged 2 to 4 months, which were allowed to
live out their lives. A few animals died during the first year, but most lived from 1 and a
half years to more than 2 years. Only one tumor was found at 14 months in a female which
had received two implantations of 100 mg pellets, and this was in the uterine horn. This
is in contrast with Kirkman's observations on the carcinogenicity of testosterone. A plea
is made for inbred lines of hamsters.
Riviere et al. [177]: Forty hamsters, 20 male and 20 female, aged 2 months, were
given pellets of 100 mg testosterone propionate and 25 mg of diethylstilbestrol dipropionate. They were kept until death. Five animals died before 11 months; the rest died later.
There were 17 leiomyosarcomas of the epididymis and 18 leiomyosarcomas of the uterus.
These were transplantable when the hosts were given estrogens or testosterone; otherwise,
there were few takes and these tumors therefore appear to be hormone-dependent. No
renal tumors, except very small epitheliomas in two or three cases, were noted. The
flank organ of these animals was enlarged, but no tumors were seen, in contrast to other
observations [122J.
Riviere et al. [175]: This is an attempt to duplicate the studies of KIRKMAN and
ROBBINS [120] who, in 1956, claimed that 'testosterone may act as a nonspecific carcinogen
in the hamster'. Forty golden hamsters, half males and half females, aged 2 to 4 months,
were given 100 mg testosterone propionate pellets subcutaneously and 6 months later
this was repeated. The third pellet was given on the 12th month and the fourth pellet on
the 18th month. In this way, the animals remained under constant testosterone action.
Only one tumor, a tubular papillary epithelioma of the uterus, was found in a 14-monthold female with 2 pellets of testosterone. No other tumors were found. A plea is made
for more careful distinction between experimentally induced and spontaneous tumors,
and the statement is made that in the golden hamster there are currently no inbred lines;
thus, in contrast to other animals such as rats and mice, one uses a material which is not
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HOMBURGER
very well known. The wish is expressed that at some time, pure inbred lines or at least
homogeneous lines of hamsters, will be available so that useful interpretation of results
of oncology in the hamster will become possible.
Riviere et al. [178]: Twenty 2-month-old male hamsters received implantation of
100 mg testosterone propionate and 25 mg of dipropionate of diethylstilbestrol. Five
months later a second series of similar pellets was implanted. Twelve to thirteen months
after the beginning of the treatment, abdominal masses were palpated and in 17 of the
20 animals there were tumors of the epididymis. The three other animals had died from
intercurrent disease. In one case, there were metastases to the lung. Histologically, these
were leiomyosarcomas or leiomyomas of the smooth muscle of the epididymis. In all
cases, the pituitary gland was markedly enlarged; the cortical adrenal gland appeared
hyperactive; the thyroid appeared hypertrophic and the testicles were atrophic with
absence of spermatogenesis. In the liver, there were multiple cysts of varying size derived
either from the hepatic parenchyma or from the biliary tract. In three animals there were
epithelial foci in the kidney which resembled the tumors described by Kirkman, but were
smaller. In those animals which received both the testosterone and the estrogen, such
tumors did not appear in Kirkman's studies; however, in the present experiment such
tumors did appear in three hamsters, but not in the others. It may be assumed that neutralization of the female hormone by the male hormone was incomplete in these cases. Why
the two hormones given together should produce tumors of the epididymis was unexplained. Given alone, testosterone causes no tumors and the estrogens cause kidney tumors
only in male animals. Transplantation of the epididymis tumor has been possible in only
one animal when the host also was treated with testosterone and estrogen. All other nine
grafts in animals so treated were negative and all grafts in untreated animals were negative.
See Russjield [185], p. 223.
Thiery [223] : This paper reports on the painting of a 1 % suspension of BP in acetone
onto the cervix under visual control which yielded results in the hamster morphologically
similar to those found in the mouse, although the time required for inducing squamouscell carcinomas in hamsters is somewhat longer than in mice.
See Tomatis [224], p. 202.
Breast Gland
See Riviere et al. [180], p. 213.
Riviere et al. [182]: While spontaneous mammary tumors of hamsters are practically
unknown there are, according to RIVIERE et al. [180] two cases, one observed by HORNING
and the other by HALBERMANN and cited by KIRKMAN [107]. Induced tumors of the mammary gland in hamsters are also rare. Only DELLA PORTA (abstract 41, p. 196) has reported
reproducible production of mammary tumors with MC
Forty female hamsters, one month of age, were used. Eighteen were painted with
urethan in a 50% solution with acetone on the shaved skin of the back, and 20 additional
animals received urethan by mouth in the drinking water at 0.2%. Approximately 15 mg
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Only occasionally have spontaneous breast-gland carcinomas been
reported in hamsters. Prolonged estrogen treatment does not appear
to cause significant changes in the hamster mammary gland. However,
breast cancers have been observed following administration of Me
by stomach tube and following urethan administered by various
routes. Induced mammary cancers were often accompanied by ovarian
tumors.
The Syrian Golden Hamster in Chemical Carcinogenesis Research
221
of urethan was thus taken daily by mouth and 125 mg were received at each painting.
Forty other female hamsters were left untreated. In the untreated hamsters there were
no tumors. Twelve to 18 months after the beginning of the treatment, six mammary
cancers appeared in the treated hamsters, four of these in the painted animals and two in
those receiving urethan by mouth. Breast cancers appeared any place in the mammary
chain and were all papillary epitheliomas. Three of these tumors have been transplanted
and are not hormone-dependent, growing in males and in females.
Riviere et al. [183]: Forty 1-month-old female hamsters were used in this experiment.
Twenty-five were painted with 50% urethan in acetone twice a week on the previously
shaved back. Twenty were given 0.2% urethan in the drinking water. In the treated
animals, there were 6 mammary tumors, 4 in the painted animals and 2 in those receiving
urethan by mouth, 12 to 18 months after the beginning of the treatment. Three were
transplanted and took. They grew independently of sex of the recipient and therefore are
not hormone-dependent. They metastasize upon transplantation to lungs and lymph
nodes. In all of the hamsters having mammary tumors, there were ovarian tumors, either
unilateral or bilateral, and these were either follicular tumors or tumors of the corpus
luteum. (Appears to the same material as in abstract 182.)
Endocrine Glands
See Dontenwil! & Bder [48], p. 205.
Dontenwil! & Mohr [56]: Thirty-one male hamsters received, after the 42nd day
of life, 3 times weekly by spray, sesame oil containing condensate described in other
papers by DONTENWILL AND MOHR as to dosage, etc. In 31 animals which lived for 12
months there were large adenomatous papillomas of the thyroid. In 13 of these animals
there were metastases of these tissues. This was described as the equivalent of human
metastatic struma, and the effect observed was ascribed to the nicotine content of the
condensate.
Fortner et al. [72]: Twenty-four of 204 hamsters fed an iodine-deficient diet of rice
and carrots developed thyroid cancer with metastasis to the lymph nodes or lungs. An
additional 57, or 28%, had probable cancer, and 121, or 59%, had thyroid hyperplasia.
Histologically, the cancers were follicular adenocarcinomas, well differentiated and
precluding the definite diagnosis of cancer in the absence of metastasis. While differentiated
metastatic cancer of the thyroid is comparable to the metastasizing struma of man, in a
second experiment using hamsters from a different source, thyroid cancer was found in
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Pituitary chromophobe adenomas are induced in male hamsters
by prolonged estrogen treatment. Radiothyroidectomy also caused
adenomas. Adrenal adenomas were also seen in some estrogen-treated
male hamsters. Testosterone also caused adrenal adenomas in some
studies.
Ovarian adenomas were present in animals fed Me by stomach
tube.
Thyroid adenomas were observed in hamsters kept on iodinedeficient diets and also occurred in hamsters treated with oral sprays
of tobacco-smoke condensate for nearly one year. The pathogenesis of
these 'tobacco-tar-induced' adenomas is obscure, since neither the
genetic nor the nutritional background of these animals was known.
HOMBURGER
only the females. In other experiments, spontaneous cancer was found in 8, or 1.5%, of
523 hamsters surviving 181 days or longer on a diet of Purina laboratory chow. These
were of two histologic types: papillary and follicular adenocarcinoma and spindle-cell
carcinoma. There were lymph node metastases. In the cancers found on the iodinedeficient diet, the neoplastic changes in the thyroid gland were diffuse, suggesting TSH
stimulation. In the spontaneous tumors observed with the Purina chow, the changes were
focal, suggesting an etiological mechanism other than TSH stimulation.
Fortner et al. [71]: Fifty male and fifty female young adult Syrian golden hamsters
were obtained from commercial breeders and were given a diet of unpolished brown
rice with fresh carrots and tap water. This was extremely low in iodine. They were
allowed to live out their life-span and then were examined. Control animals were fed a
Purina chow diet. Survival times of the 100 hamsters on the iodine-deficient diet were 36
to 685 days, with a mean of 441 days (for the males, 406 days; for the females, 474 days).
There was a weight loss. The severity of thyroid abnormality varied directly with the
time the animals had been on iodine-deficient diet. Nine of 49 females (18%) which had
metastatic thyroid cancer had been on the deficient diet for 393 to 674 days, with a mean
of 520 days. Metastases occurred only in females and no definitely demonstrable carcinomas occurred in males.
Franks & Chesterman [73]: This is an observation on 94 hamsters-36 untreated,
18 treated with stilbestrol, 21 treated with stilbestrol and receiving, in addition, implants
of MC into the dorsal prostate, 4 animals treated with MC alone, and 15 animals treated
with other hormones, with or without Me. The length of treatment ranged from 1 to
24 months, and the observations are summarized as follows: Stilbestrol treatment of the
golden hamster was followed by the formation oflarge, irregular, presumably hyperplastic
cells in the zona fasciculata of the adrenal. First changes appeared in the middle of the
zone and later involved the whole of the zona fasciculata and reticularis. After about six
months, hemorrhage and degeneration may develop with, in some cases, destruction of
the cortex. These changes sometimes resemble those seen in women dying during pregnancy or early puerperium. They also resemble certain aging changes observed in normal
hamster adrenals. While stilbestrol-induced changes were seen in breeding animals of
either sex, they were very slight or absent in the segregated males treated when young. In
two stilbestrol-treated animals, there were localized tumor nodules of the inner zones
of the cortex of the adrenal, and cortical adrenal tumors were found in two other males,
one treated with MC alone and the other with MC and stilbestrol.
Horning [97]: This paper deals with observations in rats, but also with studies in
ten male golden hamsters, beginning at the age of two weeks. The animals received
subcutaneous injections of 0.5 mg testosterone propionate in peanut oil. In 21 days, the
dose was gradually increased to 1 mg and after 6 months all the survivors were receiving
a weekly dose of 2.5 mg of testosterone for a total of 21 months. There were two adrenal
cortical tumors in the male hamsters. One was a large carcinoma and the second was a
smaller lesion which resembled that occasionally observed in rats after prolonged administration of estrogen. There were no spontaneous tumors of the adrenal in the author's
colony of old hamsters. Even after the prolonged male sex-hormone treatment, the
pituitary glands were normal in size and appearance. Reference is made to a paper by
KIRKMAN [120]. The author considers testosterone as, under certain conditions, a mild
carcinogen. The evidence presented is not too convincing.
See Harming & Whittick [93], p. 207.
See Kirkman [102], p. 217.
See Kirkman [110], p. 208.
See Kirkman & Robbins [120], p. 218.
See Riviere et al. [175], p. 219.
See Riviere et al. [178], p. 220.
See Riviere et al. [183], p. 221.
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222
The Syrian Golden Hamster in Chemical Carcinogenesis Research
223
Russjield [185]: Prolonged estrogen treatment may induce both chromophobe
adenomas of the anterior lobe and intermediate lobe tumors of the pituitary in the Syrian
hamster [93]. Twelve pituitary tumors were found in a group of male Syrian hamsters
(half castrated, half intact) implanted subcutaneously with 15 mg pellets of diethylstilbestrol at 4-month intervals and surviving more than 8 months. Six tumors, average
weight 34.5 mg, occurred in castrated animals; all were of intermediate lobe type. Six
tumors, average weight 53.9 mg, occurred in intact males. One was of intermediate lobe
type; 5 were chromophobe adenomas associated with marked intermediate lobe hyperplasia. Those animals bearing chromophobe adenomas also had adrenal changes suggestive
of early neoplasia. The marked mammary stimulation often reported in male rats bearing
estrogen-induced chromophobe adenomas was not seen in any case. FORTNER [69] has
shown that castration inhibits development of spontaneous adrenal carcinomas in the
male hamster. It is suggested that the histological differences seen in estrogen-induced
pituitary tumors in castrate and intact males may be linked with the differences found in
the adrenals.
Russjield [186]: This is an extensive monograph on hormone-induced tumors in
various species, including hamsters.
Vasquez-Lopes [227]: This paper includes an excellent review on the subject of the
development of adenoma-like hyperplasia in the pituitary body after long treatment with
estrogens. The author refers to GARDNER'S work, showing that the tendency to form
hyperplastic pituitary masses under hormonal stimulation is inherited and is not correlated
with the liability to mammary cancer in mice. Young male and female hamsters bred in the
author's laboratory were used. They received estradiol benzoate or diethylstilbestrol in
doses of 10 mg as pellets beginning at the age of about 6 weeks in one series and 4-5
months in another series. All animals that lived for more than 270 days developed enlarged
pituitaries and tumor-like masses which, histologically, were diagnosed as adenomas of
the intermediate part. (See also RUSSFIELD [185]). In one case there was metastasis of an
epididymis tumor to the kidney. This may have been the first instance of a renal tumor
produced by prolonged administration of estrogen (in this case, 299 days), but probably
it was misdiagnosed as metastasis of an epididymal tumor in this case. It was the difference
between the species, such as the guinea pig's failure to respond in the same way as mice
and rats, and the rabbit's failure to form pituitary adenomas with estrogen treatment
(although chromophobe hyperplasia is observed in a strain of rabbits with spontaneous
mammary tumors) that led the author to study this type of experiment in hamsters and
led him to the conclusion that pituitary growth in the hamster under these conditions
is regarded as essentially similar to that occurring in rats and mice in response to estrogen
treatment. The location of response is different, but the nature is the same .The borderline
between simple hyperplasia and neoplasia in the hamster is more than usually difficult, but
it was believed by VAZQUEZ-LOPEZ that the tumors observed are best described as an
adenoma-like hyperplasia of the pars intermedia analogous to similar growth of the
anterior lobe in rats and mice. The differences between this work and that of RUSSFIELD
[185] might well be explained on the basis of genetic differences between the hamsters
used.
Subcutaneous Tissue
Subcutaneous fibrosarcomas have been produced in hamsters by
and by MC and DBP administered simultaneously.
While the latent periods were about equal to those observed for
subcutaneous carcinogenesis in other rodents, there was one instance
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DBP, BP, DMBA
224
HOMBURGER
Bering& Handler [20]: Insertion of 2 em square polyethylene sheets in the subcutaneous space produced tumors of the fibrosarcomatous type 442 and 457 days after
insertion. This is nearly twice as long a time of latency as that observed in rats.
Bischoff& Bryson [21]: The subject of this paper is of a general nature and does
not deal specifically with the hamster. Hence, it is not abstracted.
Crabb [36]: The work of Crabb demonstrates the susceptibility of the hamster to
subcutaneous injection ofDMBA by development of a mixed-cell type sarcoma which was
transplantable between hamsters of different origin, but not transplantable to mice.
See Gye & Foulds [79], p. 164.
Halberstaedter [80]: This is the first paper on BP-induced tumors in the hamster,
and the similarity between the response of hamsters, rats and mice is noted. Formation of
subcutaneous sarcomas, 93% tumors; average latency, 3 months; metastasis to lymph
nodes in 72% of the animals.
Herrold [90]: The purpose of this paper was to compare the effects of subcutaneous
injections of N-methyl-N-nitrosourethane and N-methyl-N-nitrosourea. It had been
reported that the same active form, namely, diazomethane, is produced by hydrolysis of
either of these compounds. No tumors are locally induced by the subcutaneous administration of N-methyl-N-nitrosourethane to rats and hamsters. Experimental animals
were one-month-old Syrian hamsters of either sex. One group of 10 animals received
0.1-0.2 ml of the aqueous solution of N-methyl-N-nitrosourea (NMU) weekly by subcutaneous injection in the interscapular region for periods of 3-4 months. Group B
received subcutaneous injections of 0.2 ml of distilled water. The significant fact emerging
from this experiment is that the local effect produced in Syrian hamsters by the subcutaneous administration of N-methyl-N-nitrosourea is decidedly different from that of Nmethyl-N-nitrosourethane. Thus, the mechanism of carcinogenesis by these two compounds remains unclear. In addition to the subcutaneous sarcomas which invariably developed in these animals, benign tumors and hyperplastic lesions were found in the glandular stomach, forestomach, ovary and vagina. The significance of these is not clear. There
were also hyperplastic lesions associated with epithelial atypism in the palate, gingiva,
esophagus, forestomach and glandular stomach. Thus, although the same active form,
diazo methane, may be produced by hydrolysis of either of the two compounds, the mechanism of carcinogenesis by the two urea derivatives may be different.
Hirtzler [91]: This paper is important in relation to the question of whether local
application of carcinogens to various organs can produce cancers which are not caused
by the fibrous tissue reaction produced by such application. Me-soaked silk threads were
implanted into the kidneys of mice, hamsters and rats as well as into the adrenals of hamsters and rats. In the kidneys of mice, the sarcomas and one carcinoma developed after
six months. This most likely originated from the connective tissue encapsulating the
thread. The carcinoma was of renal pelvic origin. In rats and hamsters, no tumors had
developed after six months. Rats appear unsuitable for this work because of the extremely
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wherein histological observations showed malignant fibroblasts 24
hours after subcutaneous injection of Me.
N-methyl nitrosourea caused subcutaneous sarcomas at the site of
injection, while N-methyl-N-nitrosourethane did not have this effect.
Subcutaneously induced sarcomas, in most instances, metastasize
to various organs in hamsters-a phenomenon that is extremely rare
in mice and rats.
Solid state carcinogenesis operates in hamster subcutaneous tissue
as it does in rats, but apparently with longer periods of latency.
The Syrian Golden Hamster in Chemical Carcinogenesis Research
225
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intense fibrotic reaction that lead to sarcomas arising in this fibrous tissue. Hamsters
reacted very slightly or with no fibrosis, especially in the adrenals, so there is a possibility
of direct contact with the carcinogen and the epithelium. However, the time of observation (six months) appeared to be too short.
Homburger et al. [92]: The subject of this paper is of a general nature and does not
deal specifically with the hamster. Hence, it is not abstracted.
Kirkman [104]: In golden hamsters receiving testosterone together with diethylstilbestrol alone, or with progesterone, fibromas appear, often at or near the site of
testosterone injection or implantation. They occur in each sex, whether gonadectomized
or not, after about 200 days of treatment, and regress rapidly following cessation of
treatment. Whether or not they can be induced by either testosterone or progesterone
alone is not known at this time. They have not been found in males or females untreated
or injected with sesame oil or saline solution; in intact or gonadectomized males or females
reoeiving stilbestrol alone; in intact males or females given alpha estradiol; or in intact
males receiving ethinyl estradiol or Fenocylin. Ten of eleven males receiving both testosterone propionate and stilbestrol for from 271 to 543 days developed tumors. . .. The
fibromas occur subcutaneously. They are firm, silvery-white ovoids, well demarcated
from surrounding connective tissue. They are cellular in appearance, being composed of
great numbers of fibroblasts lying in a dense collagenous stroma. Mitoses are easily
found, but not abundant. As a rule the ovoid tumors are composed of cellular and fibrous
membranes so extremely crumpled as to form very intricate patterns. The tumor cells give
negative reactions to tests for fat, cholesterol, ketosteroids, acid phosphatase and glycogen.
They contain moderate amounts of alkaline phosphatase. No myofibrils have been
recognized in them.... The tumors are probably similar to those reported by Lacassagne
(1939) as spindle-cell sarcomas, occurring in male and female mice at the site of androgen
injection.
Nettleship & Smith [150]: Fibrosarcomas were produced by the injection of MC
in tricaprylin or olive oil subcutaneously. Tumors were produced in 6 hamsters by
subcutaneous injection in the right median thigh area of 0.5 mg of MC in 0.25 mg of
tricaprylin. Trocar transplants were made into 7 animals as soon as tumors appeared.
There were 100% takes. Transplants were carried through five generations and 12 animals
were used in each generation. In control experiments, olive oil or saline suspensions of
carbon black were used, and the animals were sacrificed at 24 and 48 hours, 3, 4, 7 and
10 days, and 2, 3 and 4 weeks following the injections. In summary, the subcutaneous
injection of MC into hamsters produced fibrosarcomas within 60 to 80 days. Examination
of the injection site 24 hours after injection showed fibroblasts which were morphologically
different from normal. The altered fibroblasts form a distinct strain of cells in the nodules
close to the area of injection and it is from these nodules of altered fibroblasts that invasive
fibrosarcoma grows. In contrast to the oil solutions of carcinogen used, the saline suspensions produce cell necrosis and giant cell reaction.
See Reynolds & Turner [171], p. 218.
See Riviere et al. [176], p. 219.
See Riviere et al. [179], p. 219.
Wodinsky [233]: This is a paper reporting on subcutaneous injections, 0.25 to 2 mg
per hamster ofDBP (benzo [rst] pentaphene) in tricaprylin in a volume ofOA ml. Typical
fibrosarcomas in the subcutaneous tissue were produced, with an incidence of 55% in the
smallest dose of 0.25 mg and 100% with 1 mg or more, and with an average time of
latency of 14 weeks following 0.25 mg and 9.8 or 10.2 weeks following 2 and 1 mg,
respectively. Thus, DBP is carcinogenic in the hamster.
226
HOMBURGER
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Received August, 1968
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