Abstract 954: A selective iNOS inhibitor N6-iminoethyl-lysine tetrazoleamide (NILT), suppress invasive colonic cancers and improves preventive efficacy of low-dose COX-2 inhibitor, celecoxib in F344 rats

Clinical and preclinical studies suggest that NSAIDs and cyclooxygenase (COX)-2 inhibitors such as celecoxib, reduce the risk of colorectal cancer. However, at high doses celecoxib causes gastrointestinal toxicity and an increased cardiovascular risk. Inducible nitric oxide synthase (iNOS), similar to COX-2, is overexpressed in colon tumors, and nitric oxide is shown to stimulate COX-2 activity and contributes to the tumor invasiveness. Thus, in the present study we tested a novel iNOS-selective inhibitor NILT for colon cancer inhibition and invasiveness in F344 rats and evaluated the combined low dose effects of NILT and celecoxib, to improve the chemopreventive efficacy in rats. Seven week old male F344 rats (36/group) were fed control AIN-76A diet and colon cancer was induced by administering azoxymethane (AOM), s.c., a single dose at week 8 and 9. Four weeks after the AOM treatment, groups of rats were fed experimental diets containing either 0, 100, 200 ppm of NILT or 250 and 500 ppm of celecoxib or a combination of 100 ppm NILT and 250 ppm celecoxib. Forty eight weeks after AOM treatment, rats were killed and the colonic tumors were evaluated. Multiple samples of colonic tumors from each group were assayed for activity levels of iNOS, COX-2, and expression levels of cytokines, chemokine and markers of apoptosis and cell proliferation. We found that dietary administration of 200 ppm NILT suppressed both colon adenocarcinoma incidence by 40% (p