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New medications show promise in treating drug-resistant prostate cancer
Date:4/7/2009

ress the growth of cancer cells temporarily, but in most patients the cancer ultimately develops resistance to drugs. About 29,000 men in the United States die each year from the disease.

Prostate cancer becomes resistant to antiandrogen drugs when cancer cells begin to increase production of the androgen receptor, said Sawyers. When the level of androgen receptors on the cells' surface reaches a certain level, the drugs that originally suppressed the cancer actually begin to stimulate cancer growth.

Because of this backlash effect, many scientists have questioned whether blocking the androgen receptor is a wise course of action. But Sawyers and his colleagues believe that blocking the receptor is critical to successful treatment. So they set out to design a new generation of drugs that can block the androgen receptor without unwanted side effects, even when levels of the receptor are high.

Researchers in Sawyers' lab based their designs on a drug that tightly attaches to the site on the androgen receptor that binds testosterone. If that site is blocked, the hormone cannot bind to prostate cells and tell the receptor to stimulate growth. Using this molecule as a chemical scaffold, the researchers synthesized nearly 200 slightly different versions of the drug. They tested each one in the lab on prostate cancer cells that had been engineered to produce high levels of androgen receptor.

This screening yielded two molecules, RD162 and MDV3100, which tightly bind to the androgen receptor and did not show the cancer-stimulating effect of bicalutamide and other current antiandrogen drugs. The molecules were good candidates for drugs, because they are readily absorbed into the blood when taken orally and they persist in the bloodstream.

The researchers tested the new drugs' effectiveness in mice with tumors derived from drug-resistant prostate cancer cells. "To our delight, we found that these compounds caused very dramatic shrinkage of tumors in th
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Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
Source:Eurekalert

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