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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.

"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.


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]

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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November 3, 1999; updated November 6, 1999
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