Abstract 1849: Chemopreventive efficacy of naproxen, sulindac, and their nitric oxide-derivatives in the hydroxylbutyl(butyl)nitrosamine induced model of urinary bladder cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL A variety of studies were performed with naproxen (a standard NSAID with a good cardiovascular profile), sulindac, and their nitric oxide (NO)-derivatives. In Fisher 344 rats, OH-BBN (2x/week for 8 weeks by gavage) induced invasive urinary bladder cancers. When treatment was initiated one week following the final dose of OH-BBN, both naproxen (400 ppm) and sulindac (400 ppm) were highly effective preventive agents at these human equivalent doses. The NO-derivatives of each compound (NO-naproxen, 550 ppm and NO-sulindac, 520 ppm) were similarly effective. When the dose of naproxen was decreased from 400 ppm to 75 ppm a strong preventive effect was still observed. This activity was observed even when treatment with naproxen was started 12 weeks after the last OH-BBN treatment; microcarcinomas already existed at this time. In an attempt to make a more direct comparison between the human and rat data, animals were treated with 40 mg/kg BW/day of naproxen by gavage. Similar to the dietary dose of 400 ppm, the agent was highly effective; however, gavaging the rats permitted more direct comparison of the pharmacokinetics observed in the rat with known results in humans. In contrast to the naproxen data, reducing the dose of sulindac from 400 to 150 ppm, a dose comparable to the human dose employed by Meyskens, et al. (Cancer Prevention Res. 1:32-38, 2008), resulted in only limited activity. Finally, the effects of naproxen and NO-naproxen on modulation of gene expression in the livers of treated rats were determined. Limited, but similar, gene expression changes induced by both agents were observed. Interestingly, neither agent induced the antioxidant response element genes [e.g., GST Pi, quinone oxidoreductase, aldo keto reductase A37 (aflatoxicol)] that one might have expected to be highly induced by free NO. Supported by the NCI contract number HHSN261200433001C. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1849. doi:10.1158/1538-7445.AM2011-1849