Preventive effects of NSAIDs, NO-NSAIDs, and NSAIDs plus difluoromethylornithine in

27 Urinary bladder cancer prevention studies were performed with the nonsteroidal anti28 inflammatory drugs (NSAIDs) naproxen (a standard NSAID with a good cardiovascular profile), 29 sulindac, and their nitric oxide (NO) derivatives. Additionally, the effects of the ornithine 30 decarboxylase inhibitor, difluoromethylornithine (DFMO), alone or combined with a suboptimal 31 dose of naproxen or sulindac was examined. Agents were evaluated at their human equivalent 32 doses (HEDs), as well as at lower doses. In the hydroxybutyl(butyl)nitrosamine (OH-BBN) 33 model of urinary bladder cancer, naproxen (400 or 75 ppm) and sulindac (400 ppm) reduced the 34 incidence of large bladder cancers by 82, 68 and 44%, respectively, when the agents were 35 initially given 3 months after the final dose of the carcinogen; microscopic cancers already 36 existed. NO-naproxen was highly effective, while NO-sulindac was inactive. To further compare 37 naproxen and NO-naproxen, we examined their effects on gene expression in rat livers 38 following a 7 day exposure. Limited, but similar, gene expression changes in the liver were 39 induced by both agents, implying that the primary effects of both are mediated by the parent 40 NSAID. When agents were initiated 2 weeks after the last administration of OH-BBN, DFMO at 41 1000 ppm had limited activity, a low dose of naproxen (75 ppm) and sulindac (150 ppm) were 42 highly and marginally effective. Combining DFMO with suboptimal doses of naproxen had 43 minimal effects whereas the combination of DMFO and sulindac was more active than either 44 agent alone. Thus, naproxen and NO-naproxen were highly effective, while sulindac was 45 moderately effective in the OH-BBN model at their HEDs. 46 Cancer Research. on April 2, 2017. © 2013 American Association for cancerpreventionresearch.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on December 17, 2013; DOI: 10.1158/1940-6207.CAPR-13-0164