AROMATASE AND ANDROGEN INHIBITORS IN PROSTATE CANCER

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In previous grant periods, aromatase inhibitors were developed for use in the treatment of hormone-dependent cancers. One compound, 4- hydroxyandrostenedione (4-OHA), is now being used successfully in the treatment of postmenopausal breast cancer patients. However, in preliminary studies, 4-OHA did not result in objective remission of disease in patients with metastatic prostate cancer. In an attempt to improve treatment for patients with this disease, the principal investigator has synthesized several compounds that are potent inhibitors of androgen biosynthesis (inhibiting both 17 a-hydroxylase/17,20 lyase and 5 a-reductase). They may also reduce estrogen production by limiting substrate for aromatase. The specific aims of this proposal are: 1) To synthesize and evaluate (both in vitro and in rats) steroid compounds that are more potent inhibitors of androgen biosynthesis; 2) To determine whether the most potent inhibitors cause regression of prostate cancers in the rat Dunning prostate tumor model and in athymic mice bearing PC-82 human prostate carcinoma xenografts; and 3) To determine the effects of the most potent inhibitors and newer aromatase inhibitors on androgen receptor levels and markers of programmed cell death in tumor tissue of treated mice. Effective inhibitors of androgen and estrogen biosynthesis could be of value in the treatment of prostate cancer.