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The Prostate 32:294–295 (1997)
Adenovirus-mediated Expression of
PML Suppresses Growth and
Tumorigenicity of Prostate
Cancer Cells
Dalin He, Zhao-Mei Mu, Xiaofeng
Le, Jer-Tsong Hsieh, Rey-Chen Pong,
Leland W. K. Chung, and Kun-Sang
From the Division of Laboratory
Medicine [D.H., Z-M.M., X.L., K-S.C.]
and the Department of Urology [J-T.H.,
R-C.P., L.W.K.C.], The University of
Texas M. D. Anderson Cancer Center,
Houston, Texas 77030.
Cancer Res 57:1868–1872, 1997.
Our previous studies demonstrated that the promyelocytic leukemia gene, PML, encodes a growth and
transformation suppressor. Overexpression of PML inhibits cancer cell
growth in vitro and in vivo. In this
study, we further explored the possibility of applying PML as a potential
agent for developing prostate cancer
gene therapy using an adenovirus delivery system. We have constructed
and produced the recombinant PMLadenovirus, Ad-PML, in which the fulllength PML cDNA is driven by the
strong cytomegalovirus promoter. In
LNCaP, DU145, and PC-3 prostate cancer cell lines, an infection efficiency of
90% can be achieved at a concentration
of 2, 10, and 100 multiplicity of infection (MOI), respectively. Western blotting and immunofluorescence staining
demonstrated that the AD-PMLinfected cells expressed a high level of
PML protein. The protein expression
peaked at days 3–4 postinfection, and a
detectable level of PML was found at
day 18 after viral infection. To test the
effect of Ad-PML on the growth of
prostate cancer cells, the DU145 and
LNCaP cells were infected with 10 and
2 MOI of Ad-PML. We found that the
growth rate of the Ad-PML-infected
DU145 and LNCaP cells were significantly inhibited. A tumorigenicity test
in nude mice showed that the AdPML-treated DU145 cells failed to form
tumors. Most importantly, direct injection of Ad-PML into DU145-induced
tumors was able to repress tumor
growth in nude mice by 64%. Taken
together, these data indicate that PML
is a tumor growth suppressor in prostate cancer and that Ad-PML may be a
potential candidate for human prostate
cancer therapy. (Reproduced with permission of the American Association for
Cancer Research, Inc.)
The Prognostic Value of CD44
Isoforms in Prostate Cancer
Patients Treated by
Radical Prostatectomy
Marinus A. Noordzij, Gert-Jan van
Steenbrugge, Nicole S. Verkaik, Fritz
H. Schröder, and Theodorus H. van der
From the Departments of Urology
[M.A.N., G-J.v.S., N.S.V., F.H.S.] and
Pathology [T.H.v.d.K.], Erasmus University, Post Office Box 1738, 3000 DR
Rotterdam, The Netherlands.
Clin Cancer Res 3:805–815, 1997.
CD44 forms a group of transmembranous glycoproteins formed by alternative splicing of a single mRNA.
The expression of v6 exon-containing
variants correlates with metastasis and
poor prognosis in a number of malignancies. The distribution and prognostic value of CD44s, CD44v5, and
CD44v6 were studied immunohistochemically in the radical prostatectomy specimens of 97 patients with
prostate cancer and in 12 lymph node
metastases. The mean follow-up period was 84 months. The percentage of
CD44-immunoreactive cells was scored
semiquantitatively. CD44 mRNA expression was studied in nine prostate
cancer and eight benign prostatic hyperplasia (BPH) samples by reverse
Benign prostatic glands almost
always expressed CD44s, CD44v6,
and, at a lower intensity, Cd44v5.
CD44 scores decreased from low- to
high-grade prostatic intraepithelial
neoplasia. CD44s, CD44v5, and
CD44v6 were expressed in 86, 23, and
69% of the adenocarcinomas, respectively. Gleason sum score (GSS) and pT
stage were correlated inversely with
CD44s and CD44v6 scores. CD44 was
not found in the lymph node metastatic
tumor cells. At the mRNA level, 89% of
the tumors and all BPH samples expressed CD44s. CD44v6-v10 mRNA ws
present in 44 and 75% of the tumors
and BPH samples, respectively. Loss of
CD44s and CD44v6 predicted an adverse prognosis at univariate analysis.
The independent prognosticators identified by multivariate analysis were:
GSS, pT stage, and CD44s for clinical
progression; GSS and CD44s for prostate-specific antigen progression; and
GSS for tumor-specific survival. Loss
of CD44s expression in prostate adenocarcinoma predicts a poor prognosis,
independent of stage and grade. (Reproduced with permission of the American
Association for Cancer Research, Inc.)
Cryosurgery of Prostate Cancer.
Use of Adjuvant Hormonal Therapy
and Temperature Monitoring - A
One Year Follow-up
Fred Lee, Duke K. Bahn, Timothy
A. McHugh, Anil A. Kumar, and Robert A. Badalament
From the Crittenton Hospital, Departments of Radiology [F.L., D.K.B.,]
and Surgery, [T.A.M., A.A.K., R.A.B.],
1101 W. University Drive, Rochester,
MI 48307, U.S.A.
Anti Cancer Res 17:1511–1516, 1997.
Objective: To determine the clinical outcomes at one year of Stages T2T3 prostate cancer by cryosurgery utilizing pretreatment with total androgen ablation therapy and temperature
monitoring to control the freezing process. Study Group: To date, 347 patients have had 356 cryosurgical procedures. 280 have reached one year post
treatment. Of these, 131 had reevaluation with prostatic biopsy and
serum PSA. Methods: Transrectal ultrasound (TRUS) measurement of tumor size and biopsy of extraprostatic
space was used to stage patients into
two main groups: confined (66.6%) versus nonconfined (19.3%). Radiation
failures (14.1%) formed a separate
group. Failure rates for the 131 men include all cancer diagnosed during the
one year period following cryosurgery.
Results: The one year failure rate for
the study group was 19.8% (26/131).
For stages T2a, T2b C, T3 and radiation
failures, the rates of positive biopsies
were 13.9%, 12.9%, 33.3% and 35%, respectively. For those with local control
of cancer (negative biopsy), 80% had
prostate specific antigen (PSA) levels of
<0.5 ng/ml. The statistical variables for
persistent cancer with prostate specific
antigen >0.5 ng/ml were: sensitity of
66.7%, PPV of 16.7%, NPV of 98% and
specificity of 83.7%. A statistically significant difference exists between
stages T2 vs T3 and radiation failures
(p = <0.5). Major complications of rectal fistula and total incontinence for
previously non-treated cancer versus
radiation failures were 0.33% and 8.7%
respectively, a 26 times greater risk.
Conclusion: Results of cryosurgery for
all stages of prostate cancer at one year
are encouraging, being 80% free of disease (biopsy and prostate specific antigen). The morbidity of the previously
non-treated cancers from this procedure for us was minimal with high
patient acceptance. For radiation failures a local control rate of 65% was
achieved. However, early in our experience significant morbidity did occur
and our enthusiasm for attempted salvage was initially tempered. (Reproduced with permission of the International
Institute of Anticancer Research.)
Apoptosis in Rat Prostatic
Adenocarcinoma is Associated With
Rapid Infiltration of Cytotoxic
T-Cells and Activated Macrophages
Maréne Landström and Keiko
From the Department of Pathology, University of Umeå [M.L.], Ludwig Institute for Cancer Research, Biomedical Center, Uppsala, Sweden
[M.L., K.F.]
Int J Cancer 71:451–455, 1997.
Rats transplanted with the androgen-sensitive, syngeneic Dunning
R3327 PAP prostatic tumor were castrated and treated with estrogen or vehicle for 4, 12 and 24 hr and for 6
weeks. Tumor growth was retarded by
castration and further inhibited by estrogen. Immediately after castration,
an increased number of activated macrophages and T-cells were found in
parallel with increasing apoptotic tumor cells. Administration of an immunosuppressive drug, FK 506, abolished
the growth-inhibitory effects of castration and estrogen. The tumor growth
rate correlated negatively with the
number of R73- and OX8-positive Tcells and NK cells and with the percentage of ED3-positive macrophages.
There was a positive correlation between the percentage of TdT-mediated-dUTP nick end labeling (TUNEL)positive apoptotic cells and that of
ED3-positive cells. Our results suggest
that apoptosis of prostatic carcinoma
cells induced by endocrine treatment in
vivo is partly due to a rapid infiltration
by immunocompetent cells. Int. J. Cancer 71:451–455, 1997. © 1997 Wiley-Liss,
Inc. (Reprinted by permission of WileyLiss, Inc., a subsidiary of John Wiley &
Sons, Inc.)
Polymorphic Repeats in the
Androgen Receptor Gene:
Molecular Markers of Prostate
Cancer Risk
Janet L. Stanford, Jeanette J. Just,
Mark Gibbs, Kristine G. Wicklund,
Cassandra L. Neal, Brent A. Blumenstein, and Elaine A. Ostrander
From the Divisions of Public
Health Sciences [J.L.S., K.G.W., B.A.B.]
and Clinical Research [J.J.J., C.L.N.,
M.G., E.A.O.], Fred Hutchinson Cancer
Research Center, Seattle, Washington
Cancer Res 57:1194–1198, 1997.
We analyzed the polymorphic
(CAG)n and (GGN)n regions within the
androgen receptor gene from participants in a population-based casecontrol study of prostate cancer in
middle-aged (40–64 years) Caucasian
men. The associations between repeat
lengths and risk of prostate cancer and
the effects of confounding and modifying factors, such as age, family history
of prostate cancer, and body mass index, were evaluated. DNA was avail-
able for 301 cases and 277 controls. The
overall age-adjusted relative odds of
prostate cancer associated with the
number of (CAG) repeats as a continuous variable was 0.97 [95% confidence
interval (CI), 0.92–1.03], suggesting a
3% decrease in risk of prostate cancer
for each additional (CAG) repeat. Further analyses identified several subgroups at increased risk. These were
men with less than the median number
of CAG repeats (<22) that were
younger [<60 years; relative odds (RO),
1.47; 95% CI, 0.96–2.25], had an affected
first-degree relative (RO, 1.59; 95% CI,
0.62–4.14), or were relatively thin
(Quetelet index <24.4; RO, 2.21; 95%
CI, 1.07–4.69). Although only the latter
result was stastistically significant,
these results are provocative and support the hypothesis that (CAG)n array
length is a predictor of risk for prostate
cancer. Similar analyses of (GGN)n
showed that with the exception of men
with a family history of prostate cancer
and those in the highest quartile of
body mass index, men with ø16 repeats had higher risk estimates than
did men with >16 repeats. Overall,
those men who had ø16 repeats had a
significant elevation in risk (RO, 1.60;
95% CI, 1.07–2.41). When both repeat
lengths were considered jointly, the
subgroup with two short repeats
(CAG, <22; GGN, ø16) had a 2-fold elevation in odds (RO, 2.05; 95% CI, 1.09–
3.84) relative to those with two long
repeats (CAG, ù22; GGN, >16). These
data suggest that determination of
both androgen receptor repeats within
germ-line DNA may be useful in assessing an individual’s risk of developing prostate cancer. (Reproduced with
permission of the American Association for
Cancer Research, Inc.)
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