We have discovered several potent inhibitors with dual activities against testicular 17alpha-hydroxylase/C17,20-lyase and prostatic 5alpha-reductase which could be useful in the treatment of prostatic cancer. We now wish to optimize their activities against 5alpha-reductase while retaining inhibition of 17alpha-hydroxylase/C17,20-lyase. The emphasis of this renewal application is to pursue our important leads, identify the most active compounds and complete preclinical evaluation of them in a series of new systems we have established.
The specific aims of the proposal are to synthesize inhibitors of 17alpha-hydroxylase/C 17,20-lyase with enhanced 5alpha-reductase inhibition. New compounds will be evaluated as inhibitors of human testicular 17alpha-hydroxylase/C17,20-lyase and prostatic 5alpha- reductase, including Type I and Type II isoforms. We will determine whether inhibitors cause enzyme inactivation or are converted to active androgens, affect other steroidogenic enzymes including 3beta- hydroxysteroid dehydrogenase/isomerase, 17beta-hydroxysteroid dehydrogenase, the cholesterol side-chain cleavage enzyme and the adrenal 17alpha-hydroxylase/C17,20-lyase. Potential agonistic or antagonistic properties of the potent inhibitors will be determined on both the human wild type androgen receptor (AR) and the mutant AR in transcriptional activation assays. To determine the effect of inhibitors on prostatic growth, cell cultures and histocultures of human prostates will be carried out. Gram quantities of the most active inhibitors ot date and potent new inhibitors will be prepared for further evaluation in vivo. The effects of the most potent inhibitors will be then studied in animal models in vivo in normal adult rats and nude mice with human prostatic PC-82 tumors. Prostate and tumor weights, and plasma and tissue concentrations of androgens will be measured. In addition, the efficacy of treatment will be determined by investigating proliferation, apoptosis and expression of androgen-dependent genes in histoculture of human prostates and tumors from the nude mice treated with inhibitors.
