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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