Prostate cancer is currently the most common malignancy in American males and the second leading cause of cancer mortality in this population. It is estimated that in 1991, 122,000 new cases of prostate cancer will be diagnosed in the U.S. and 33,000 patients will succumb to this disease. Biologically, prostate cancer displays some unique characteristics: (a) It is a slow-growing tumor and its doubling time has been estimated to be in excess of two years. (b) Autopsy studies reveal the presence of histological prostate cancer in a staggering 30% of all males older than 50 years. The vast majority of these cancers never progress to clinically manifest disease, but the ones who do, cannot, at the present time, be identified as such in advance. The prolonged preclinical and clinical course of prostate cancer, as well as the high prevalence of histologic prostate cancer in the elderly population, suggests that the tumor lends itself well to a strategy of early pharmacological intervention with the intent of """"""""chemoprevention"""""""". However, before a large scale clinical chemoprevention trial is engaged upon, the potential pharmacological/chemopreventive agents need to be tested for efficacy in prostate cancer. We will conduct a preclinical trial using an oncogene-induced prostate cancer in the mouse prostate reconstitution (MPR) model to test the efficacy and elucidate the mechanism of action of alpha- difluoromethyornithine (DFMO), a polyamine synthesis inhibitor. The MPR model will also be used to test for synergism between the cancer suppression effect of DFMO and that of fenretinide (4-HPR), a retinoid prototype, and to test the ability of finasteride (Proscar), a 5alpha- reductase inhibitor, to serve as a chemopreventive agent for prostate cancer. In addition, we will use the animal model to test the hypothesis that pretreatment with these differentiation agents (DFMO and 4-HPR) can enhance the subsequent response to androgen ablation therapy. Finally, we will conduct a phase II trial in prostate cancer patients using 4-HPR, DFMO, and finasteride to examine the effect of these agents in human prostate cancer. The proposed project will lay the foundation for subsequent, large scale, phase III clinical trials using these agents at specific critical periods in the course of prostate cancer.
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