Abstract 962: Similar preventive effects of naproxen and NO-naproxen in a chemically-induced model of urinary bladder cancer: Dose dependency, gene expression and toxicity

Abstract

Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) have been highly effective in preventing colon, urinary bladder, and skin cancers preclinically; and also in clinical trials of colon adenoma formation. However, certain NSAIDs cause gastrointestinal (GI) ulceration and may increase cardiovascular (CV) events. Naproxen appears to cause the lowest CV events of the common NSAIDs other than aspirin. NO-naproxen was tested based on the finding that adding a nitric oxide (NO) group to NSAIDs may help alleviate GI toxicity, as well as the expectation that the production of NO itself might be therapeutically effective. We examined these agents in the hydroxybutyl(butyl)nitrosamine (OH-BBN) rat urinary bladder cancer model beginning 2 weeks after the last dose of carcinogen. Naproxen at doses of 400, 200, 128 or 75 ppm in the diet greatly decreased the development of large urinary bladder cancers. NO-naproxen at 183 or 550 ppm caused striking decreases in the incidence of large tumors implying that both agents are similarly effective. The lower doses of these agents are well below the human equivalent dose based on standard scaling factors. We are presently treating rats with naproxen by gavage and collecting serum to directly compare the pharmacokinetics of naproxen in the rat and human. To determine whether there was any indication of NO release in NO-naproxen treated rats, microarrays were performed with liver and bladder tissues from treated rats. Minimal differences in gene expression changes between the two agents were observed. Also, an ARE related response in the liver, which one would have expected from NO, was not seen. Thus, the data are compatible with limited direct effects of NO on urinary bladder cancer prevention. Supported by the NCI contract number HHSN261200433001C. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 962.