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Anti-androgen agents may stimulate prostate cancer cells in certain cases of advanced disease

Prostate cancer cells that survive hormonal therapy with an anti-androgen agent may be stimulated later through a different mechanism by the same drug, according to an article in the November issue of Cancer Research. The experiments, which demonstrated that anti-androgen agents actually turn on an enzyme known to cause cancerous cells to grow, was given an award for outstanding research from the American Urological Association.

"It's a real surprise, that the same compound that kills cancer cells also makes them grow," says Chawnshang Chang, Ph.D., a coauthor. "The effect of the drug reverses completely."

Treatment for men with metastatic prostate cancer has been based on the testosterone dependence of tumor cells. After surgery, radiation, and other treatment options are exhausted, doctors try chemical or surgical castration or hormonal therapy to suppress testosterone activity. Treatment often includes use of an anti-androgen, which blocks the androgen receptor.

However, clinicians also know that cancer cells typically become receptor negative after one or two years and begin growing again. Usually, doctors remove these patients from the anti-androgen, and they improve temporarily before the cancer takes over again.

Yi-Fen Lee, Ph.D., lead author, and his colleagues studied cancer cells from four men, comparing cells from early in the disease with cells sampled after hormonal therapy became ineffective. The team found that an enzyme known as MAP kinase was present at much higher levels in the cells that had survived hormone therapy. Later work showed that anti-androgen agents turn on production of the enzyme, a cell growth promoter known to play a role in both breast and prostate cancer.

The finding explains at least part of the reason why drugs like hydroxyflutamide, the anti-androgen the team studied, suddenly switch from being effective to being ineffective. Furthermore, the scientists said, the compound triggers molecular signals that do not involve the androgen receptor itself --- meaning that its effect on MAP kinase and cell growth stimulation is independent of its androgen receptor antagonism.

"In all of the more than 30,000 men who die of prostate cancer each year, the cancer cells have become capable of growing even when we starve the cells of testosterone," said Edward Messing, M.D., another coauthor. "In each one of those men, there's been a fundamental change, so that the molecule we've targeted for stopping the cancer is no longer involved in the disease. It's at this point that the disease becomes a killer. Finding an additional potential target for preventing this switch is surprising and significant."

The authors hope that clarification of the mechanism underlying anti-androgen withdrawal syndrome will lead to a new drug target and more effective therapy for men with late-stage prostate cancer.



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