In Vivo Molecular Effects of Prostatic COX-2 Inhibition

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DESCRIPTION (provided by applicant): The proposal addresses the potential role of pharmacologic inhibition of the cyclooxygenase-2 enzyme (COX-2) for prostate cancer prevention or treatment, There is compelling evidence from in vitro experimental studies that inhibition of COX-2 decreases cellular proliferation, increases apoptosis, and modulates genes involved in cell cycle regulation. Additionally, observational epidemiologic studies find reduced risks of prostate cancer among men using nonsteroidal anti-inflammatory drugs, COX-2 inhibitors. One of the theories on how these compounds exert their effects is through protection from reactive oxygen species and subsequent DNA damage, while others have postulated that these agents modulate the cell cycle. Several groups currently are continuing intensive studies examining the in vitro effects of various COX-2 inhibitors on CaP cell lines or in CaP xenografts, however, no human experimental studies have examined the effects of COX-2 inhibitors on prostate tissue biology, This proposal is based on the hypothesis that COX-2 inhibition will reduce levels of intraprostatic prostaglandins, reduce oxidative stress, and modulate genes controlling the cell cycle in prostate tissue. The hypothesis will be tested in two double-blinded, placebo-controlled, randomized clinical trials to test effects of 25mg of the COX-2 inhibitor rofecoxib (Vioxx() on prostate biology: the first among men with a biopsy positive for cancer scheduled for prostatectomy within 6 weeks; the second among men with a prostate biopsy negative for cancer scheduled for repeat biopsy in 6 months. Tissues and blood collected at the initial biopsy will be compared with those collected post-treatment, allowing an assessment of both the acute (4 weeks) and chronic (6 months) effects of COX-2 inhibition. All analyses are based on modeling the treatment intervention effect, defined as the changes in cancer-related endpoint measures from baseline to follow-up in the active drug arm minus the placebo arm. The results of these investigations will clarify the impact of COX-2 inhibition on prostate biology, reveal mechanisms underlying the effects of COX-2 inhibitors on prostate cancer risk, and identify other pathways and targets for future primary and secondary prostate cancer prevention trials.