The long-term objective of our research is to identify innovative strategies for colon cancer prevention and to apply the knowledge from preclinical efficacy studies to use with individuals at high-risk for colon cancer as a means of prevention. Current evidence suggests that a diet rich in n-3 polyunsaturated fatty acids (n-3 PUFAs) and cyclooxygenase (COX)-2 inhibitors, such as celecoxib suppress azoxymethane (AOM)-induced colon carcinogenesis in F344 rats. Although colon tumor inhibition by COX-2 inhibitors is much more effective than traditional NSAIDs, high doses of COX-2 inhibitors have caused some side effects in humans. The preclinical experiments proposed in this application will provide compelling evidence that the aggregate action of n-3 PUFA-rich diet in combination with a COX-2 inhibitor, celecoxib would be significant, while side effects induced by the COX-2 inhibitor would be minimized. The proposed studies will evaluate two hypothesis: a) There is synergism in the mechanisms of action of COX-2 inhibitors and n-3 PUFAs, the former inhibiting carcinogenesis through modulation of generation of eicosanoids, angiogenesis and apoptosis while the latter suppressing colon carcinogenesis through NO pathways, cell differentiation and apoptosis, b) the combination of a diet rich in n-3 PUFAs with a COX-2 inhibitor will increase the efficacy by modulating synergistically the above molecular parameters.
The specific aims are: 1) Determine the efficacy of a low dose of celecoxib administered in n-3 PUFA rich diet as compared when a high dose of this agent administered in a high-fat, Western style diet containing mixed lipids in AOM-induced colon carcinogenesis in F344 rats. 2) Determine the combined effects of celecoxib administered in n-3 PUFA-rich diet on colon cancer-related genes in colonic mucosa and tumors of rats. We will focus on apoptotic genes, Bcl-2, NF?B and on the eicosanoid- and NO-pathways including COX-2, LOX, and iNOS and their interactions with other functional groups of genes in colon carcinogenesis using DNA microarrays, RT-PCR and Western Blot analysis. Clear delineation of the synergistic effects in preclinical models will allow the rational design of human clinical trials.
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