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New Hormonal Therapy Research
Challenges Conventional Thinking
on Ways to Treat Prostate Cancer
November 6, 1999 /PSA Rising/ --New York.-- For decades, physicians have known that male hormones fuel prostate
cancer growth. Androgen withdrawal, also called androgen deprivation therapy (ADT) or hormonal blockade, is a standard treatment for prostate
cancer. Androgen withdrawal results in a decrease in tumor volume and a decline in serum
PSA (prostate-specific antigen) in most patients.
At one time surgical castration (orchiectomy) was used to achieve androgen deprivation, sometimes in combination with doses of the female hormone estrogen. Then came a new generation of hormonal blockading drugs.
Today, therapies that block the production of androgen - or testosterone - provide some
of the most effective treatments for men with advanced prostate cancer. Hormonal blockading drugs are standardly prescribed to cause
the PSA level to fall and shrink tumors. But despite initial success with a series of first- and second-line therapies that block
testosterone production or stop it from "docking" in cell receptors, eventually prostate tumors return and are resistant to further hormonal treatment.
Now, research conducted by Memorial Sloan-Kettering Cancer Center raises new questions about why
existing therapies don't stop the disease from returning. The findings, published in the November 3rd issue
of the Journal of the National Cancer Institute, challenge current thinking about how to treat prostate
cancer. The investigators say that their study "dovetails" with recent research by Memorial Sloan-Kettering investigators
that offers new strategies to treat this lethal form of the disease.
In the current study, the investigators evaluated the effectiveness of hormonal
therapy to treat human prostate cancer in mice. They found that withdrawing testosterone caused the
majority of the tumor cells to go into a dormant, or growth arrested state, but that very few cells died. They call it a "cell stress response." "Changes in apoptosis (programmed cell death)," the investigators write in their abstract, "were not observed at any time after androgen
withdrawal." They say in the article:
"Apoptotic changes were
not observed after androgen withdrawal. Characterization of the androgen-independent phenotype revealed
the overexpression of mdm2, affecting p53 stability, as well as the increased cyclin D1 expression, affecting
pRB phosphorylation. These results challenge a commonly held view that the regression of prostate cancers
after androgen withdrawal is mediated exclusively by apoptotic mechanisms. Furthermore, the results
suggest that therapeutic strategies directed at the cell cycle-arrested prostate cancer cells, after androgen
withdrawal, may be clinically important." Journal of the National Cancer Institute, Vol. 91, No. 21, 1869-1876,
November 3, 1999
For more details see excerpt below.
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"Until now we thought that blocking the production of testosterone killed most of the prostate cancer cells
and that the few remaining 'resistant' cells were what caused the disease to recur. But this study suggests
that few cells die after testosterone is blocked," said Dr. Howard Scher, Chief of Genitourinary Oncology at
Memorial Sloan-Kettering Cancer Center and senior author of the study in the Journal of the National
Cancer Institute.
To find out more about why therapies that block the production of testosterone ultimately fail to prevent a recurrence
of prostate cancer, the researchers injected mice with human prostate cancer cells. The cells injected came from the hormone-sensitive CWR22 prostate cancer xenograft (this new strain of cells is being used today to check the genetics of prostate cancer and find new therapies).
Once the disease had developed in the test mice, the researchers withdrew testosterone. Biopsying tumors in a series of mice implanted with clone-identical human prostate cancer cells allowed the investigator to monitored changes in the cancer over time and look for sequential effects of testosterone withdrawal. They found that there was an initial increase in the activity of proteins that control the growth of tumor cells. But instead of causing all the tumor cells to die, the proteins appeared merely to inactivate the cells, or to stop them from growing.
"We found that the increase in these proteins reflected an initial cell stress response that stopped the
majority of the cells from growing. But ultimately the prostate cancers came back because cell death did not
occur," said Dr. David Agus, an oncologist at Memorial Sloan-Kettering Cancer Center and lead author of the
study. "The next step is to develop drugs that will target the growth arrested prostate cancer cells."
This research was supported in part by the National Cancer Institute, the Eleanor and Paul Stephens Foundation, the American Cancer
Society, the PepsiCo Foundation and CaP CURE.
This research appears in Journal of the National Cancer Institute, Vol. 91, No. 21, 1869-1876, November 3, 1999. To read the online abstract, click the title
Prostate Cancer Cell Cycle Regulators:
Response to Androgen Withdrawal and Development of
Androgen Independence
David B. Agus, Carlos Cordon-Cardo, William Fox, Marija Drobnjak, Andrew Koff, David W. Golde,
Howard I. Scher
To read the full article you need a subscription or access through Loansome Doc or a medical library. Medical journals are usually available through Interlibrary loan. The excerpt below includes footnotes which we have linked, where possible, to online abstracts of the articles cited.
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The "Discussion" section of the article includes a summary of controversy over apoptosis (programmed cell death). Our footnotes link to a selection of the references cited
The current dogma is that androgen withdrawal in prostate cancer will result in
the apoptotic death of a majority of cancer cells and that the few remaining cells
are resistant and will grow back with an androgen-independent phenotype.
Characterization of the androgen-independent phenotype has been limited by
the lack of biopsy material from these patients. The CWR22 xenograft model
recapitulates a subset of human prostate cancers in that, after androgen
withdrawal, there is a decline in PSA levels. This decline is followed by regression of the tumor, a rise in PSA
levels, and then regrowth as an androgen-independent neoplasm (2).In this study, we categorized changes
in cell cycle regulators after androgen withdrawal as early and mid-to-late events. The early cell cycle events
were consistent with a cellular stress response associated with an increase in p53, followed by an increase in
p21, and a transient early G1/G0-phase arrest, as shown by a decrease in Ki67 expression and a reduction in
the number of cells in S phase. The lack of an apoptotic response during this period is consistent with the
low-to-undetectable levels of bax and bcl-2 proteins. These data suggest that the growth arrest observed
after androgen withdrawal is the result of a failure to activate cell death mechanisms in this xenograft model
and that activating p53-independent cell death signals may be an important strategy to effect a complete
response to androgen withdrawal.
..... Conflicting results have been observed in human
prostate cancers after androgen withdrawal, since increased levels of apoptosis have been reported by some
groups of investigators (21-23) but not by other groups (24-27). The apparently contradicting results may
reflect the small proportion of cells actually undergoing apoptosis at any one time, the inability to sample
tumors repeatedly at different times, or the small overall contribution of apoptotic cell death to human tumor
regression. An alternative explanation is that the cell cycle checkpoint status of the various tumors is
different. The integrity of the checkpoint status can change the response to anticancer therapy from cell
cycle arrest to cell death in the xenograft model system (28).
2.Nagabhushan M, Miller CM, Pretlow TP, Giaconia JM, Edgehouse NL,
Schwartz S, et. al. CWR22: the first human prostate cancer xenograft
with strongly androgen-dependent and relapsed strains both in vivo and
in soft agar. Cancer Res 1996;56:3042-6. [abstract]
21.Montironi R, Pomante R, Diamanti L, Magi-Galluzzi C. Apoptosis in prostatic adenocarcinoma following
complete androgen ablation. Urol Int 1998;60 Suppl 1:25-9. [abstract]
22.Denmeade SR, Lin XS, Isaacs JT. Role of programmed (apoptotic) cell death during the progression
and therapy for prostate cancer [published erratum appears in Prostate 1996;28:414]. Prostate
1996;28:251-65. [abstract]
23.Reuter VE. Pathological changes in benign and malignant prostatic tissue following androgen
deprivation therapy. Urology 1997;49(3A Suppl):16-22.
[abstract]
24.Westin P, Stattin P, Damber JE, Bergh A. Castration therapy rapidly induces apoptosis in a minority
and decreases cell proliferation in a majority of human prostatic tumors. Am J Pathol
1995;146:1368-75. [abstract]
25.Murphy WM, Soloway MS, Barrows GH. Pathologic changes associated with androgen deprivation
therapy for prostate cancer. Cancer 1991;68:821-8.
[abstract]
26. Dhom G, Degro S. Therapy of prostatic cancer and histopathologic follow-up. Prostate
1982;3:531-42.[abstract]
27.Tomic R, Bergman B, Hietala SO, Angstrom T. Prognostic significance of transrectal fine-needle
aspiration biopsy findings after orchiectomy for carcinoma of the prostate. Eur Urol
1985;11:378-81. [abstract]
28.Waldman T, Zhang Y, Dillehay L, Yu J, Kinzler K, Vogelstein B, et al. Cell-cycle arrest versus death in
cancer therapy. Nat Med 1997;3:1034-6. [abstract]
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Have you checked the links to online cancer journals listed on on our PCa Research page? Some of them are worth a bookmark.
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