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The NSAID sulindac was previously suggested for colon cancer prevention based on the inhibition of hereditary and sporadic colonic adenomas in humans. However, while sulindac inhibited tumors in the small intestine and increased tumors in the large intestine of Min and Apc1638 mice (9 weeks and 6 months of feeding respectively) it induced severe inflammation, and benign and malignant colonic tumors in wild type C57Bl/6 mice within 6 months of feeding (AACR Proceeding 46:1427, 2005). A Western-style diet alone also induced chronic inflammation and colonic tumors in C57Bl/6 mice after 18 months of feeding (Carcinogenesis 22:1871-1875, 2001). To further study the relationships of genotype, diet, inflammation and colon tumor development, A/J mice were fed the following four diets: 1) AIN-76A control diet; 2) sulindac (200ppm) premixed in AIN-76A; 3) NWD, new Western-style diet (AACR Proceeding 47: 1353, 2006); and 4) sulindac (200ppm) premixed in NWD. Within 1-2 months neoplastic lesions including focal areas of dysplasia (FAD) and microtubular adenomas were seen in 89% of A/J mice fed sulindac in AIN-76A and in 95% of mice fed sulindac in NWD; at 10 months of feeding these lesions developed in 53% of mice fed NWD alone, and no lesions occurred in mice fed AIN-76A diet. Multiplicity of neoplasms was 2.39 and 3.00 per mouse in the two sulindac groups respectively and 0.63 in NWD, P<0.001. Neoplasms occurred in cecum (83%), duodenum (56%), proximal colon (17%) and (0%) in distal colon of mice fed sulindac in AIN-76A; and 89%, 68%, 37% and 16% respectively of mice fed sulindac in NWD. Mice fed NWD alone had neoplasms mainly in cecum (42%), duodenum and distal colon (5%), and proximal colon (0%). Sulindac further exacerbated inflammation of the intestine during this short feeding duration in all A/J mice studied. The scores of inflammatory severity (degree x depth of inflammatory infiltration into intestinal wall) were cecum (14.39), duodenum (6.11), proximal colon (2.00) and distal colon (0.28) in mice fed sulindac in AIN-76A (P<0.001, and <0.01 in the cecum and duodenum vs. AIN-76A). In mice fed NWD inflammatory severity was also significantly increased in the cecum (7.00) vs. AIN-76A control (1.50, P<0.01). Findings indicate that A/J mice fed (1) NWD diet alone, (2) sulindac in AIN-76A or (3) sulindac in NWD are highly susceptible to the rapid development of inflammation and tumor-related endpoints. Thus, A/J mice may be useful for studying the effects of genotype and the modulation of inflammatory and tumor endpoints by chemopreventive agents.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA