Sulindac Reversal Of 15-Pgdh Mediated Resistance To Colon Tumor Chemoprevention With Nsaids

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer development by inhibiting cyclooxygenase (COX) enzymes responsible for the production of tumor growth promoting prostaglandins. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a colon tumor suppressor that degrades prostaglandins and antagonizes COX-mediated oncogenesis. Deletion of 15-PGDH in mice results in an increased susceptibility to azoxymethane (AOM)-induced colon tumor formation and resistance to the chemopreventive effects of the COX-2 selective inhibitor, celecoxib. Similar resistance to colon adenoma prevention with celecoxib has been shown in humans with low colonic 15-PGDH levels. In this study, we expanded the panel of NSAIDs tested in a mouse colon tumorigenesis model to include sulindac and aspirin to determine if these non-selective COX-1 and COX-2 inhibitors would be a better treatment for the prevention of colon adenomas in mice genetically lacking 15-PGDH. Materials and Methods: 15-PGDH wild-type and knockout mice on a FVB/NJ background were administered azoxymethane (AOM) by i.p. injection once per week for 6 weeks at 10mg/kg dose. Concurrent with the first AOM injection, all mice were fed for the length of the study with either a control (AIN-76A) diet or diet supplemented with celecoxib (1250 ppm), sulindac (167 ppm), or aspirin (300 ppm). Mice were euthanized 14 weeks after the last AOM injection, and the colons were removed and examined under a dissecting microscope to identify all tumors and inflammatory lesions. The effect of NSAID treatment on COX inhibition was determined by measuring colonic PGE2 levels. Results: We demonstrate a significant difference in tumor formation between aspirin and sulindac treated 15-PGDH knockout mice compared to celecoxib treatment. Sulindac significantly prevented colon tumor formation while aspirin had no protective effect, despite a comparable reduction in colonic mucosal PGE2 levels by both sulindac and aspirin. Additionally, we find that treatment of celecoxib or sulindac for an extended period of time results in a significant increase in colonic inflammation in both wild-type and knockout mice, with lymphoid aggregates and large proximal colon inflammatory lesions appearing, and that the incidence of inflammatory lesions correlate with NSAID efficacy. Conclusions: These findings suggest sulindac may be the most active NSAID for colon chemoprevention in populations with low 15-PGDH, but raise the caution that this agent may also give rise to inflammatory lesions in the colon. Citation Format: Stephen P. Fink, Dawn M. Dawson, Yongyou Zhang, Adam Kresak, Earl G. Lawrence, Peiying Yang, Yanwen Chen, Jill S. Barnholtz-Sloan, Joseph E. Willis, Levy Kopelovich, Sanford D. Markowitz. Sulindac reversal of 15-PGDH mediated resistance to colon tumor chemoprevention with NSAIDs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2815. doi:10.1158/1538-7445.AM2015-2815