The translational goal of this project is to identify host characteristics that can be used toindividually tailor colon cancer prevention therapy in order to reduce the development of clinically significantcolorectal intraepithelial neoplasia (IEN) in humans with elevated risk for colon cancer. The hypothesis to be tested in this proposal is that individual responses to certain colon cancerpreventive agents, including specific non-steroidal anti-inflammatory drugs (NSAIDS) and agents that targetfeatures of polyamine metabolism, are influenced by host factors, including genetic background, and diet.
Three specific aims are proposed to test this hypothesis. First, we will determine if genetic variability inthe host gene encoding ornithine decarboxylase (ODC) can explain individual variability in colorectalmucosal polyamine contents. We will also determine if variability in the ODC and/or the flavinmonooxygenase 3 (FM03) genes modulate the action and/or bioavailability of the chemopreventive agentssulindac and difluoromethylornithine (DFMO) when given in combination for the reduction of colon polyprecurrence. Second, we will determine if the association between the ODC G316A promoter variant allelesand adenoma recurrence in aspirin users involves other genes, which affect polyamine metabolism.
This aim will focus on the spermidine/spermine N1-acetyltransferase (SSAT), and determine if acetylated polyamines,which are substrates for polyamine export, may be a useful biomarker of NSAID action. Third, we will assessthe independent and joint effects of aspirin use,dietary sources of polyamines, and gene modifiers ofpolyamine synthesis (ODC) on risk of colorectal adenoma recurrence. We will pool data from three adenomarecurrence studies, including the Polyp Prevention Trial (PPT), Wheat Bran Fiber (WBF) andUrsodeoxycholic Acid (UDCA) colon polyp prevention trials to assess these effects on overall adenomarecurrence and recurrence of advanced lesions.The long-term goal of this project is to determine the influence of host and adenoma factors as predictors ofefficacy for the chemoprevention of colorectal adenomas, particularly advanced, clinically significant lesions,and to use this information to reduce the incidence of colorectal cancer in individuals with high risk ofdeveloping this disease.
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