A Preclinical Chemopreventive Model in Prostate Cancer

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DESCRIPTION (provided by applicant) A number of clinical studies are underway to test agents that may prevent or delay the progression of prostate cancer (CaP). While preliminary results are intriguing, mechanistic evidence supporting their effectiveness and dosimetric data identifying optimum treatment regimens is lacking. In addition, many studies are being performed in animals to develop biomarkers and screen potential chemotherapeutic agents, with little understanding of their validity for CaP. We therefore believe that there is a critical need for a standardized model to investigate the effectiveness, safety and molecular mechanisms involved in CaP chemoprevention. It is our hypothesis that by using a CaP model to classify chemopreventive agents according to mechanism of action, we will be able to develop therapeutic regimens that maximize the potential for reducing prostate tumor growth. The purpose of this application is to develop such a model with rats by inducing CaP with the prostate carcinogen PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) in combination with testosterone treatment. PhIP has been chosen as the model compound because it has human relevance: it is present in the human diet, has been detected in human tissues, and may help explain the higher CaP incidence in African Americans relative to Caucasians. Specifically we will: (1) Determine the histopathological changes occurring in the rat prostate during PhIP-induced tumorigenesis and determine whether intermediate changes can be defined at the histological and molecular level; and (2) Assess whether selected chemopreventive agents reduce DNA adduct levels and reduce tumor formation and/or change tumor growth. Once developed, this model will be used to study, which putative chemoprotective agents actually do cause a reduction in prostate cancer and determine the most effective treatment schedule including assessment of single agent and combination therapy, prior to investing in human studies. In addition, the model will be useful for identifying interactions between drugs, diet and chemoprevention treatments, and will ultimately provide a means to study the pharmacology and toxicology of chemopreventive agents. This model will also be useful for studying the importance of diet in prostate cancer, both from a causation and chemoprevention standpoint. Use of such a model should lead to faster development of effective treatment options or lifestyle change recommendations by virtue of focusing research investment on those areas, which have actually demonstrated the ability to affect prostate carcinogenesis.