PPAR GAMMA AGONISTS FOR THE PREVENTION OF COLON CANCER

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Epidemiological studies strongly associate non-steroidal anti- inflammatory drug (NSAID) use with reduced risk for colon cancer. NSAIDS prevent colon cancer. However, alternative explanations may exist. Certain NSAIDS are ligands for peroxisome proliferator-activated receptors (PPARs), members of the nuclear receptor superfamily of transcription factors. The overall investigating agonists of PPAR gamma as possible chemopreventives for colon cancer. Colon cancer is the second cancer. The hypothesis to be tested is that agonists of PPAR gamma, a form of PPAR highly expressed in the colon epithelium and colon tumors, will be chemopreventive for he colon. I propose two aims to test the hypothesis, protein expression in rat colon epithelium. Effects on normal and colon carcinogen-treated rodent colon will be explored. We will test troglitazone, pioglitazone, rosiglitazone, BRL 49653 and the anti-inflammatory NSAIDs, indomethacin and ibuprofen. Results from these studies will provide a direct link between the reportedly elevated expression levels of PPAR gamma in the colon and compounds that activate it. In Aim 2, we will determine in the rat colon using inhibition of aberrant crypt foci (ACF) as an intermediate endpoint. These studies are aimed at determining whether PPAR gamma agonists are inhibitors of tumorigenesis in vivo. Secondary studies will assess the effects of these compounds on colonic cell proliferation and apoptotic rates. These studies will define PPAR gamma as a possible target for chemopreventive drug development.