) Aspirin (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) are prototypical colon cancer chemopreventive agents. They affect key parameters of colonic epithelial cell turnover such as cell division and cell death, in vitro and in vivo. These may be integral processes by which NSAIDs inhibit the development of colorectal neoplasms. It is conceivable that other colon cancer chemopreventive agents share these potential mechanisms of action as well. Plant foods such as fruits and vegetables have anti-neoplastic effects in several organ systems, including the colon. Though the number of active anti-cancer ingredients contained within these foods are likely abundant, the plant-derived phenolic compounds such as curcumin, rutin, and quercetin, are particularly compelling compounds to study. These compounds possess colon cancer chemopreventive properties, notably in animal models of carcinogen induced colon cancer. They antagonize tumor cell proliferation in vitro. Intriguingly, they also have biochemical properties similar to the NSAIDs. They inhibit cyclooxygenase (COX) catalytic activity and also inhibit another major arm of arachidonic acid (AA) metabolism, lipoxygenase (LOX) activity. This application outlines a clinical research study that will treat human volunteers with above average risk for colorectal cancer, i.e. those who have had colon adenomas in the past, for ten weeks with a controlled metabolic diet and one of the plant phenolic compounds: curcumin, rutin, or quercetin; or the NSAID sulindac. Serial colon mucosal biopsies will be taken from the volunteers in order to determine the effect of these compounds on colonic epithelial cells. Whether these compounds: a) affect biomarkers in the colonic mucosa that measure epithelial cell turnover, cell mass homeostasis, and cell differentiation; b) influence colonic mucosal AA metabolism; and c) produce changes in these parameters similar to sulindac, a classical, chemopreventive agent, will be determined. It is anticipated that the results of this study will provide a clearer insight into the process of colon carcinogenesis and colon cancer chemoprevention by both the NSAIDs and natural plant-derived compounds.
