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Publicationof the InternationalUnion Against Cancer
Publicationde I'Union InternationaleContre 1e Cancer
Int. J. Cancer: 65,870-874 (1996)
0 1996 Wiley-Liss, Inc.
SOMATOSTATIN ANALOG RC-160 INHIBITS THE GROWTH OF HUMAN
OSTEOSARCOMAS IN NUDE MICE
Jacek PIN SKI',^, Andrew V. SCHALLY~,~,~,
Gabor HALMOS~,~,
Karoly SZEPESHAZI',~
and Kate GROOT'
'Endocrine, Polypeptide and Cancer Institute, VeteransAffairs Medical Center, and 2Departmentof Medicine, Tulane University
School of Medicine, New Orleans, LA 70146, USA.
We investigated the effects of the potent somatostatin analog
RC-160 on the growth of human osteosarcoma cell lines SKES- I and MNNG/HOS, transplanted into nude mice or cultured
in vitro. Growth of SK-ES-I and MNNG/HOS tumors in nude
mice was significantly inhibited after 4 weeks of treatment with
daily S.C. injections of 100 pg RC-160, as measured by a
reduction in tumor volume and weight. Histologically, the
number of mitotic cells was decreased in the groups treated
with RC- 160. In mice bearing either tumor model, administration of RC- I60 significantly decreased serum growth hormone
and insulin-like growth factor I (IGF-I) levels. Specific highaffinity receptors for somatostatin and epidermal growth factor
were found on membranes of MNNG/HOS tumors but not on
SK-ES- I tumors. Receptor analyses also demonstrated highaffinity binding sites for ICF-I on membranes of both tumors. In
cell cultures, the proliferationrate of MNNG/HOS cells, but not
of SK-ES- I, was significantly suppressed by RC- 160. Our findings
demonstrate that RC- I60 can significantly inhibit the growth of
SK-ES-I and MNNG/HOS osteosarcomas in mice.
o 1996 Wiley-Liss, Inc.
@s-Tyr-D-Trp-Lys-Val-Cyk-Trp-NH2
(RC-160; Octastatin),
have been synthesized in our laboratory and shown to inhibit
the growth of experimental pancreatic, prostatic, colorectal,
gastric and mammary carcinomas (Pinski et al., 1994; Schally,
1988). Somatostatin analogs also reduced local proliferation of
experimental chondrosarcomas in vivo (Redding and Schally,
1983; Reubi, 1985).
In this study, we have evaluated the effect of somatostatin
analog RC-160 on the growth of the human osteosarcoma cell
lines SK-ES-1 and MNNG/HOS in vivo and in vitro. The 2 cell
lines, MNNG/HOS and SK-ES-1, were chosen because they
are representative of malignant human bone tumors, well
characterized and known to proliferate in vitro and to develop
tumors in athymic nude mice (Bloom, 1972; Rhim et al., 1975).
MATERIAL AND METHODS
Peptides
Somatostatin analog RC-160 (D-Phe-C$s-Tyr-D-Trp-Lys-Val-QhOsteogenic sarcomas represent the most common type of Trp-NH2) was made by classical synthesis by Novabiochem
primary bone tumor in children and young adults (Rosen, (Laufelfingen, Switzerland) and supplied by Debiopharm (Lau1993). Surgery, radiation and chemotherapy are of limited sanne, Switzerland). For daily injections, RC-160 was diseffectiveness in the treatment of osteosarcomas, and other solved in 0.1% DMSO in saline solution.
therapeutic approaches must be explored. Insulin-like growth Animals
factor-I (IGF-I) is a potent stimulant of human and murine
Male athymic (NCr nulnu) nude mice, approximately 6
osteosarcoma cell growth (Fournier et al., 1993; Kappel et al.,
1994; Lopaczynski et al., 1993; Pirskanen et al., 1993; Pollak et weeks old on arrival, were obtained from NCI (Bethesda, MD)
al., 1990, 1992; Raile et al., 1994; Scheven et al., 1991). Most of and maintained under pathogen-limited conditions. Their care
the circulating IGF-I is produced in the liver, where transcrip- was in accord with institutional guidelines.
tion of the IGF-I gene is positively regulated by growth Studies on tumor growth
hormone (GH) (Pollak et al., 1990,1992). It has been demonIn the first experiment, xenografts were initiated by S.C.
strated that the receptors for IGF-I are present on osteogenic injection of 1 x lo7SK-ES-1 cells into the right flanks of 5 male
sarcomas (Fournier et at., 1993; Kappel et al., 1994; Lopaczyn- nude mice. Tumors resulting after 4 weeks were aseptically
skietal., 1993; Pollaketal., 1990,1992; Raileetaf, 1994). It has dissected and mechanically minced; 3-mm3 pieces of tumor
also been shown that proliferation of human and murine tissue were transplanted S.C. by trocar needle into 20 mice
osteosarcomas in cell cultures i s enhanced by the addition of under methoxyflurane anesthesia. One week after transplantaIGF-I (Fournier et al., 1993; Kappel et al., 1994; Lopaczynski et tion, when tumors had grown to a volume of approx. 20 mm3,
al., 1993; Pirskanen et al., 1993; Pollak et al., 1990, 1992; Raile mice were randomized and divided into 2 experimental groups
et al., 1994; Scheven et al., 1994). GH can likewise exert a direct of 10 animals each, which received the following treatments for
stimulatory effect on the growth of human osteosarcoma cells 4 weeks: (i) daily saline injections only, control, or (ii) RC-160,
in vitro (Scheven et al., 1991).
injected S.C. at a daily dose of 100 pg/day/animal.
In view of these findings, the aim of a potential therapy
In the second experiment, xenografts were initiated by S.C.
could be to inhibit GH release from the pituitary to lower GH injection of 1 X lo7 MNNG/HOS cells into nude mice.
and IGF-I levels. The benefit of this strategy is supported by Developed tumors were transplanted into 20 mice, and the
the inhibitory effect of hypophysectomy on the metastatic experiment was carried out as described above.
behavior of a murine osteosarcoma (Pollak et al., 1992).
Tumors were measured with calipers, and tumor volume was
Somatostatin analog RC-160 also inhibits metastatic behavior calculated as length X width x height x 0.5236, as described
of RIFl osteosarcomas in mice (L. Wallace, personal commu- previously (Redding and Schally, 1983). At the end of the
nication).
treatment period, treated animals and control mice were
Somatostatin and its analogs inhibit the release of G H as anesthetized with methoxyflurane and killed by decapitation.
well as the secretion or action of growth factors such as IGF-I
and epidermal growth factor (EGF) (Schally, 1988). Signifi3Towhom correspondence and requests for reprints should be sent,
cant decreases in basal and arginine-stimulated serum G H and
IGF-I levels were noted in patients with neoplasms potentially at VA Medical Center, 1601Perdido Street, New Orleans, LA 70146,
dependent on IGF-I who received a somatostatin analog USA. Fax: (504) 566-1625.
(Pollak et al., 1989). Superactive octapeptide analogs of
somatostatin with a long duration of action, such as D-PheReceived: November 6,1995.
871
HORMONAL SUPPRESSIONOF OSTEOSARCOMAS
Trunk blood was collected and centrifuged, and serum was
frozen for hormone studies. Tumors were carefully cleaned
and weighed, and samples were taken for histology and
receptor studies.
Histologicalprocedures
A part of each tumor was fixed in 10% buffered formalin.
Specimens were embedded in Paraplast (Oxford Labware, St.
Louis, MO). Six-micrometer-thick sections were cut and stained
with hematoxylin-eosin. Mitotic and apoptotic cells were
counted in 10 standard high-power microscopic fields containing, on the average, 300 cells, and their numbers per 1,000 cells
were accepted as the mitotic and apoptotic indices, respectively.
Radioimmunoassays (RLA)of IGF-I and GH
All serum samples for IGF-I determination were extracted
by a modified acid-ethanol method described earlier (Breier et
al., 1991). Serum IGF-I levels were determined using antiIGF-I anti-serum (UB3-189) provided by the National Hormone and Pituitary Program of the National Institute of
Diabetes and Digestive and Kidney Diseases at the final
dilution of 1:14,000. IGF-I (a gift from Genentech, South San
Francisco, CA) was iodinated by the Chloramine-T method.
IGF-I standards in the range of 8-2,000 pg/tube were calibrated against WHO 1st International Reference Reagent
1988, IGF-I 87/518, supplied by the Nichols Institute (San
Juan Capistrano, CA).
Serum GH levels were determined by double-antibody RIA
using materials supplied by NIDDK. Inter-assay and intraassay coefficients of variation were less than 15% and lo%,
respectively.
Receptor assay
Receptors for somatostatin, EGF and IGF-I on the membranes of SK-ES-1 and MNNG/HOS tumors were measured
as previously described (Srkalovic et al., 1989; Szepeshazi et al.,
1992). Characteristics of somatostatin receptors were determined in competitive binding experiments using the radioligand [1251]RC-160as described previously (O’Byrne et al.,
1994). The LIGAND PC computerized curve-fitting program
of Munson and Rodbard (1980) was used to determine the
types of receptor binding, dissociation constant (&) values
and the maximal binding capacity (Bmaw)
of receptors.
In vitro studies
The human osteosarcoma cell lines SK-ES-1 and MNNG/
HOS were obtained from the ATCC (Rockville, MD). SKES-1 was grown as a monolayer in McCoy’s 5a medium
supplemented with 15% FBS, antibiotics and antimycotics.
MNNG/HOS was grown as a monolayer in MEM supplemented with 10% FBS, antibiotics and antimycotics. Cultures
were incubated at 5% C 0 2 in air at 37°C. Cells from 7040%
confluent cultures were seeded into Costar (Cambridge, MA)
’24-well plates at a density of 5 x lo3cells/well. After 48 hr (day
0), media were replaced with fresh media containing RC-160
in concentrations of 10-11-10-6 M. The cell number for each
well was determined in a Coulter (Hialeah, FL) counter after
detachment of cells by trypsinization on day 4. Cell viability,
measured by Trypan blue exclusion, was more than 90%.
Statistical methods
Statistical analyses of the data were performed using Duncan’s new multiple range test (Steel and Torrie, 1976) and
Student’s 2-tailed t test. All p values are based on 2-sided
hypothesis testing.
RESULTS
Effect of RC-160 on growth of osteosarcomas in nude mice
There were no significant differences in body weights between treated and control groups at the end of the experi-
1
Iooo
A -0-
T
Control
800
m
-
-,,,
600
28!
400
E
E
I
z
2
200
0
0
2
1
3
4
3
4
WEEKS OF TREATMENT
0
1
2
WEEKS OF TREATMENT
FIGURE1 - Tumor volumes in athymic nude mice bearing S.C.
transplanted (a) SK-ES-1 and (b) MNNG/HOS human osteosarcomas during treatment with somatostatin analog RC-160 administrated by daily S.C. injections at a dose of 100 kg/animal/day.
Treatment was started when tumors measured approximately
16-22 mm3 and lasted for 4 weeks. Vertical bars represent S.E.;
*p < 0.05, **p < 0.01 vs. control.
ments. In experiment I, after 3 weeks of treatment, the tumor
volume of SK-ES-1 osteosarcomas in the group receiving
RC-160 was significantly ( p < 0.05) reduced to 134.1 k 54.0
mm3 as compared with the control group (479.6 f 121.4 mm3),
corresponding to a 72% decrease in tumor volume (Fig. la).
The final tumor volume and tumor weight were significantly
( p < 0.01) diminished in animals treated for 4 weeks with
RC-160 to 210.3 f 71.7 mm3 and 0.25 f 0.1 g, respectively,
compared with those for controls (764.0 f 167.3 mm3 and
0.78 2 0.1 g) (Table I).
In experiment 11, RC-160 therapy similarly inhibited the
growth of MNNG/HOS tumors (Fig. lb). The mean tumor
volume and weight were significantly ( p < 0.05) reduced in
animals receiving RC-160 for 4 weeks to 455.3 f 71.8 mm3and
PINSKI ETAL.
872
TABLE I - EFFECT O F TREATMENT FOR 4 WEEKS WITH SOMATOSTATIN ANALOG RC-160 ON BODY AND
TUMOR WEIGHT AND FINAL TUMOR VOLUME IN NUDE MICE BEARING XENOGRAFTS O F THE HUMAN
OSTEOSARCOMA CELL LINES SK-ES-1 AND MNNGIHOS
Tumor volume (mm')
Treatment group
Experiment I (SK-ES-1)
Control
RC-160
Experiment I1 (MNNGiHOS)
Control
RC-160
Body weight (g)
Tumor weight (g)
764.0 t 167.3
210.3 t 71.72
25.2 f 1.0
24.6 f 0.9
0.78 f 0.1
0.25 t 0.1'
925.2 t 66.0
455.3 f 71.8*
24.8 t 0.8
23.5 f 0.5
1.0 t 0.2
0.48 0.06l
Initial
Final
22.6 t 3.6
21.3 t 3.8
16.3 t 1.5
20.0 f 1.7
*
Values are means + S.E.-lp < 0.05, ' p < 0.01 vs. control.
TABLE I1 - SERUM GROWTH HORMONE (GHI AND INSULIN-LIKE
GROWTH FACTOR I (IGF-I) LEVELS IN NUDE MICE WITH XENOGRAFTS
O F THE HUMAN OSTEOSARCOMA CELL LINES SK-ES-1 AND MNNGIHOS
AFTER TREATMENT WITH SOMATOSTATIN ANALOG RC-160
~~
~~~~
Treatment group
Exoeriment I (SK-ES-11
'
kontrol
RC-160
Experiment 11 (MNNGIHOS)
Control
RC-160
GH (nglml)
IGF-I (ngiml)
12.0 k 1.8
3.6 t 0.5*
374.6 t 81.1
95.4 t 12.8l
8.8 f 2.3
4.5 + 0.4l
316.6 f 45.1
185.2 f 10.1'
Values are means +- .S.E..Jp < 0.05, ' p < 0.01 vs. control.
0.48 f 0.06 g compared with those in the control group, which
were 925.2 2 66.0 mm3 and 1.0 r?T 0.2 g, respectively (Table I).
Histological findings
Histologically, SK-ES-1 tumors were composed of undifferentiated, large polygonal cells arranged close to each other.
Cells had narrow cytoplasms and round, large nuclei with
prominent nucleoli. Necrotic foci could be found in all tumors.
The mitotic index value showed a slight and statistically not
significant decrease in tumors treated with RC-160 (4.8 t 1.0
vs. 7.8 f 1.4 in controls). The ratio of apoptotic to mitotic
indices was significantly ( p < 0.01) higher in SK-ES-1 tumors
receiving RC-160 (4.36 t 2.6 vs. 1.9 r?T 0.31 in controls).
MNNG/HOS tumors were highly cellular. Tumor cells were
arranged without any special orientation. Cytoplasms were
slightly basophilic. Nuclei of tumor cells were large, round,
elongated in some areas and contained prominent nucleoli. No
signs of differentation or osteoid formation could be observed.
The mitotic index value decreased significantly ( p < 0.05) to
14.0 2 2.0 in tumors treated with RC-160 as compared with the
control group (22.5 t 3.7). The ratio of apoptotic to mitotic
indices in MNNG/HOS tumors was significantly ( p < 0.05)
increased by treatment with RC-160 at the end of the experiment (0.81 t 0.15 vs. 0.36 +- 0.07 in controls).
Serum hormone levels
Serum G H and IGF-I levels in control nude mice and in
animals treated with RC-160 in both experiments are shown in
Table 11. Therapy with RC-160 significantly reduced serum
GH levels to 3.6 0.5 ngiml in experiment I ( p < 0.01) and to
4.5 t 0.4 ngiml in experiment I1 ( p < 0.05), as compared with
controls (12.0 2 1.8 ngiml and 8.8 f 2.3 ngiml, respectively).
Treatment with RC-160 also significantly ( p < 0.05) decreased serum IGF-I concentrations in animals bearing SKES-1 tumors, to 95.4 12.8 ngiml, and in mice with MNNGi
HOS tumors, to 185.2 ? 10.1, as compared with controls
(374.6 2 81.1 ngiml and 316.6 f 45.1 ngiml, respectively)
(Table 11).
*
Receptor findings
The binding characteristics of receptors for somatostatin,
IGF-I and EGF in SK-ES-1 and MNNGiHOS tumors were
analyzed following treatment with somatostatin agonist RC160, and the results are presented in Table 111. Receptor assays
on SK-ES-1 tumor membranes showed high-affinity binding
sites for IGF-I (&: 0.7 2 0.01 nM), but the receptors for
somatostatin and E G F were absent (Table 111). The concentration of IGF-I receptors was significantly ( p < 0.01) increased
by treatment with RC-160 to 249.5 -C 4.9 fmolimg protein, as
compared with the control group (154.2 ? 6.1 fmolimg
protein), while the affinity of receptors was not changed
(& = 0.7 t 0.01 nM). High-affinity binding sites for IGF-I
were also found on MNNGiHOS control tumors (& = 0.48 f
0.08 nM) and RC-160-treated tumors (& = 0.76 t 0.17 nM).
A significant ( p < 0.05) increase in binding capacity (Bma)of
IGF-I receptors was again observed after treatment with
RC-160, from 74.9 2 5.9 fmolimg protein found in the control
tumors to 113.3 f 20.3 fmol/mg protein. Receptor assays on
membranes of MNNGiHOS tumors also demonstrated highaffinity binding sites for somatostatin (& = 9.52 ? 0.05 nM)
and E G F (& = 0.88 f. 0.08 nM). Therapy with RC-160 significantly ( p < 0.01) increased the binding capacity of receptors
for somatostatin on membranes of MNNG/HOS tumors by
about 85% (Table 111). A significant ( p < 0.05) reduction in
binding capacity (Bmax)of E G F receptors was observed after
treatment with RC-160, from 251.1 ? 10.3 fmolimg protein
found in control tumors to 85.0 2 3.37 fmolimg protein in
tumors treated with RC-160 (Table 111).
Effect of RC-160 on cellularproliferation
The proliferation of MNNGiHOS cells was significantly
( p < 0.01) inhibited by RC-160 at 10-*o-10-6 M concentrations (Fig. 2). At concentrations of lo7 and lo6 M, RC-160
decreased the proliferation of MNNGiHOS cells by 30.4%
and 43.6%, respectively, as compared with controls (Fig. 2).
Proliferation of SK-ES-1 cells was not affected by RC-160 at
concentrations of 10-11-10-6 M (not shown).
DISCUSSION
Our findings demonstrate that somatostatin agonist RC-160
can significantly inhibit growth of the xenografts of both
osteosarcoma cell lines in vivo. Anti-neoplastic actions of
somatostatin agonists may involve multiple mechanisms. A
significant fall in G H levels induced by RC-160 could, through
mechanisms involving suppression of endogenous growth factors, particularly IGF-I, be of major importance for the
inhibition of tumor growth. IGF-I has been shown to play an
important role in growth of osteosarcomas (Fournier et al.,
1993; Kappel et al., 1994; Lopaczynski et al., 1993; Pirskanen et
al., 1993; Pollak et al., 1990, 1992; Raile et al., 1994; Scheven et
al., 1991). Stimulatory effects of IGF-I on the proliferation of
various human and murine osteosarcoma cell lines have been
clearly demonstrated (Fournier et al., 1993; Kappel et al., 1994;
Lopaczynski et al., 1993; Pollak et al., 1990, 1992; Raile et al.,
1994). The growth of some osteosarcoma cell lines could be
inhibited in vitro by monoclonal antibodies and anti-sense
HORMONAL SUPPRESSION OF OSTEOSARCOMAS
873
TABLE I11 - BINDING CHARACTERISTICS OF SOMATOSTATIN,EGF AND IGF-I RECEPTORS IN MEMBRANES
OF SK-ES-1AND MNNGIHOS TUMORS AFTER IN VIVO TREATMENT WITH SOMATOSTATINANALOG RC-160
Somatostatin
EGF
IGF-I
Experiment I (SK-ES-1)
Control
ND
ND
ND
ND
0.7 f 0.01
RC-160
ND
ND
ND
ND
0.78 f 0.09
Experiment I1 (MNNG/HOS)
Control 9.52 f 0.05 699.1 f 13.4 0.88 f 0.08 251.1 f 10.3 0.48 2 0.08
RC-160 13.1 f 0.05 1293.1 f 160.22 0.55 f 0.03l 85.0 f 3.372 0.76 +- 0.17
154.2 2 6.1
249.5 f 4.92
74.9 f 5.9
113.3 & 20.3'
< 0.01 vs. control. N.D., not detectable. Binding
Values are means 2 S.E.-lp < 0.05,
characteristics were obtained from 10-point displacement experiments in triplicate tubes.
3500
1
*
*
*
*
*
U
3z
W
0
Y
CONTROL
-11
-10
-9
-8
-7
-6
LOG CONCENTRATION (M)
FIGURE
2 - Anti-proliferative effect of somatostatin analog RC160 on MNNG/HOS cells in vitro as measured by cell number.
Cells were cultured in the presence of RC-160 in concentrationsof
lo-" to
M. Vertical bars represent S.E.; *p < 0.01 vs. control.
oligonucleotides to the IGF-I receptor (Kappel et al., 1994;
Pollak et al., 1990; Raile et al., 1994).
Our finding of high-affinity binding sites for IGF-I in
membranes of MNNG/HOS and SK-ES-1 tumors is in agreement with previous reports by other groups on the existence of
high-affinity receptors for IGF-I in various human and murine
osteogenic sarcoma cell lines (Fournier et a/., 1993; Kappel et
al., 1994; Lopaczynski et a/., 1993; Pollak et a/., 1990, 1992;
Raile et al., 1994). IGF-I and IGF-I1 bind with different
affinities to the type-I IGF receptor, which is thought to
mediate the biological effects of both ligands through tyrosine
kinase-type activity (Fournier et al., 1993). We observed that
chronic treatment of nude mice with RC-160 increased the
concentration of IGF-I receptors of both osteosarcoma tumors. This might reflect a compensatory process caused by
suppression of the endocrine or local production of IGF-I
induced by the somatostatin analog.
RC-160 might also inhibit growth of osteosarcomas through
the suppression of the release of GH itself. GH was found to
stimulate proliferation of the human osteogenic sarcoma cell
line SaOS-2 in vitro (Scheven et al., 1991), and these effects
were abolished by an anti-IGF antibody, suggesting that G H
acted by increasing the autocrine production of IGFs (Scheven
et al., 1991).
Since high-affinity receptors for somatostatin are present on
MNNG/HOS tumor membranes, somatostatin agonist RC160 could also directly inhibit the growth of MNNG/HOS
cells. In our study, the proliferation of MNNG/HOS cells in
vitro, but not that of somatostatin receptor-negative SK-ES-1
cells, was suppressed by RC-160. Somatostatin and its analogs
stimulate tyrosine phosphatase and promote the dephosphorylati'on of EGF receptors (Buscail et al., 1994; Liebow et
al., 1989). We have shown that somatostatin agonist RC-160
produced a great reduction in the concentration of EGF
receptors on membranes of MNNG/HOS tumors. Thus, the
ability of MNNGiHOS tumor cells to respond to transforming
growth factor (Y and EGF could have been decreased in our
study. This down-regulation of E G F receptors in MNNG/
HOS osteosarcomas after therapy with RC-160 is in agreement
with similar findings in other tumors (Liebow et al., 1989;
Pinski et at., 1994; Schally, 1988). The inhibitory effect of
RC-160 on the growth of SK-ES-1 tumors in vivo observed in
our study is probably mainly due to suppression of G H and
IGF-I secretion since we did not find somatostatin receptors
on membranes of this tumor. However, the fact that our assay
did not detect somatostatin receptors on membranes of SKES-1 tumors may also be explained by the existence of several
somatostatin receptor subtypes (Bell and Reisine, 1993; Buscail et al., 1994). Molecular cloning revealed the presence of 5
structurally related integral membrane glycoproteins, which
are pharmacologically distinct high-affinity somatostatin receptors with different regional distributions and functions (Bell
and Reisine, 1993; Buscail et al., 1994). Pharmacological
studies on the characteristics of somatostatin receptors showed
that the different subtypes exhibit major differences in their
affinities for structural analogs of somatostatin (Bell and
Reisine, 1993; Buscail et al., 1994). In our study, 1251-labeled
RC-160, which is more selective for SSTR-2 and SSTR-5
subtypes (Buscail et al., 1994), was used as a tracer in
radioreceptor assays. Thus, the fact that we found somatostatin receptors on MNNG/HOS osteosarcomas and failed to
detect them on SK-ES-1 tumors may be due to different
binding affinities of RC-160 to various subtypes of somatostatin receptor.
However, our receptor results indicate a significant increase
in the concentration of binding sites for somatostatin on
membranes of MNNG/HOS tumors treated with the somatostatin analog. The finding that 4 weeks of administration of
RC-160 did not produce a down-regulation of somatostatin
receptors indicates that this therapy could be applied for
prolonged periods of time. This lack of down-regulation of
somatostatin receptors after therapy with RC-160 is also
similar to findings observed in other tumors (Srkalovic et aL,
1989; Pinski et al., 1994). In conclusion, our results suggest that
somatostatin analogs, such as RC-160, might find clinical
applications in the treatment of patients with osteogenic
sarcomas.
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