BIOCHEMICAL EFFECTORS OF GENE MUTATED IN COLON CANCER

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APPLICANT'S DESCRIPTION: The long-term objective of this research is to develop rational and non-toxic strategies for colon cancer chemoprevention, based on mechanisms of colon carcinogenesis. The central hypothesis to be tested in this proposal is that proteins affecting polyamine, prostaglandin and/or nitric oxide metabolism are biochemical effectors of colon cancer risk associated with mutations in the APC and p53 tumor suppressor genes and the Ki-ras oncogene. Altered levels of polyamines, prostaglandins and/or nitric oxide then facilitate colonic carcinogenesis by modulating the expression of other genes and metabolic processes, which in turn direct specific neoplastic cell behaviors, including apoptosis. A corollary of this hypothesis is that post-initiation strategies for colon cancer prevention will require more than one intervention. Another corollary is that intestinal luminal factors, such as polyamines derived from enteric bacteria and/or dietary sources, may be risk factors, and dietary arginine may be an antagonist, of colon cancer in humans. The Specific Aims of the proposal are to determine the mechanisms responsible for the altered expression of specific genes involved in polyamine, prostaglandin and nitric oxide metabolism, as a consequence of mutations in the APC and p53 tumor suppressor genes and the Ki-ras oncogene; to compare the effects of inhibitors of polyamine, prostaglandin and nitric oxide metabolism alone and in combination on intestinal and colonic carcinogenesis in genetically altered rodent models of colon carcinogenesis; to measure the effects of dietary supplements, including polyamines and arginine, alone or in combination with inhibitors of polyamine, prostaglandin and nitric oxide metabolism on colon carcinogenesis in genetically altered rodent models; and to determine the consequences of specific mutations, chemopreventive drugs and/or dietary supplements on the expression of genes involved in the metabolism of, and contents of, polyamines, prostaglandins, ceramide and arginine in colonic mucosal tissues and relate changes in these parameters to specific cell behaviors, including apoptosis. These studies are relevant to a number of current and future clinical cancer chemoprevention trials, including those employing non-steroidal anti-inflammatory drugs (NSAIDs) and inhibitors of polyamine synthesis.