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Patients with long-standing ulcerative colitis (UC) are at an increased risk for colorectal carcinoma development. Overproduction of LTB4 and PGE2 induced by inflammation and oxidative stress plays an important role in inflammatory cell recruitment, cell proliferation, cell survival, and carcinogenesis. Studies in UC patients have indicated that COX2 inhibition may exacerbate UC, possibly through the shunting arachidonic acid to the 5-LOX-LTB4 pathway that leads to an increase in inflammatory cell recruitment and epithelial injury. In order to overcome the toxicity of COX2 inhibition, we tested the effects of the low dose combination of COX2 and 5-LOX inhibitors on UC-induced carcinogenesis in a mouse model. Female C57BL/6 mice were subjected to long-term, cyclic dextran sulfate sodium (DSS) treatment and fed a 2-fold iron-enriched diet to induce UC and its associated carcinogenesis. The COX2 and 5-LOX inhibitors were administered in the diet. In the DSS-plus-2 fold iron positive control group, colorectal adenocarcinoma incidence was 56.5% (13/23 mice) after 12 cycles of DSS treatment. With administration of Celecoxib: 200 ppm and 500 ppm, tumor incidence was significantly inhibited (25%, 6 of 24 mice with tumors in the 200 ppm celecoxib treatment group; and 0%, 0 of 20 mice with tumor in the 500 ppm treatment group). With administration of Zileuton: 500 ppm and 1,000 ppm, tumor incidence was also significantly inhibited (28%, 7 of 25 mice with tumor in the 500 ppm Zileuton treatment group; and 16%, 4 of 25 mice with tumors in the 1000 ppm treatment group). The low dose combination of Zileuton and Celecoxib presented a much more significant inhibition of UC-induced colorectal carcinoma development (8%, 2 of 25 mice with tumor) as compared with their each low dose control groups. Although the mice treated with high doses of Celecoxib showed 100% inhibition of carcinoma development, the mice exhibited significantly larger mucosa ulcer formation and active inflammation in the colon as compared to the DSS-plus-2 fold iron positive control mice and 5 mice died early due to large ulcer. The mice treated with Zileuton or the low dose combination of Zileuton and Celecoxib displayed comparable grading of inflammation in the colon as that in DSS treated positive mice. Further mechanistic studies showed that the inhibition of UC-induced carcinogenesis by these inhibitors might relate to their function on the modulation of inflammation activity and cell proliferation. This study indicates that combination of COX2 and 5-LOX inhibitors may have the potential to serve as preventive agents for chronic inflammation-driven carcinogenesis. (Supported by NIH R01 CA104741)

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