Abstract LB-457: Effect of naproxen and NO-naproxen on intestinal neoplasia in the Apc +/Min-FCCC mouse model

Abstract

Recent efforts to improve the vascular and gastrointestinal safety of nonsteroidal anti-inflammatory drugs (NSAIDs) have included the addition of a nitric oxide-donating moiety. The ability of the common NSAID naproxen and nitric oxide (NO)-naproxen to inhibit azoxymethane-induced aberrant crypt foci in the rat colon has been demonstrated. However, the chemopreventive activity of these agents against spontaneous colorectal tumors has not been reported. The goal of the present study was to compare the ability of naproxen and NO-naproxen (low- and high-dose molar equivalents) to inhibit colorectal adenomas in a unique strain of mice (Apc+/Min-FCCC) that spontaneously develops multiple colorectal tumors. Male Apc+/Min-FCCC mice (50 days of age) were randomized (n = 17 per group) to receive control diet or diet supplemented with naproxen (132 or 400 ppm) or NO-naproxen (182 or 550 ppm) for 45 days. Body weights were recorded weekly and did not differ significantly among treatment groups. At sacrifice, small intestinal and colonic tissues were examined grossly and the entire colon was submitted for histopathologic analysis. Low-dose naproxen and low-dose NO-naproxen decreased the multiplicity of gross small intestinal adenomas by 70.3% (mean ± SEM – 9.9 ± 1.45, P = 0.04) and 64.0% (12.0 ± 1.9), respectively, as compared to that of control mice (33.3 ± 14.0). No additional benefit was obtained by administering a higher dose of either agent. Histopathologic analyses revealed that the incidence of colorectal adenomas in mice treated with naproxen (low dose – 70.6%; high dose – 64.7%) was significantly less than that of both control mice (100%) (P = 0.019 and 0.0076, respectively) and mice treated with NO-naproxen (low dose – 88.2% and high dose – 100%). Low-dose naproxen reduced the multiplicity of colorectal adenomas by 41.5% as compared to control (mean ± SEM, 1.8 ± 0.5, 3.1 ± 0.7, respectively), while the efficacy of all other treatments was less. Interestingly, treatment with high-dose naproxen caused a dramatic (89.3%) reduction in the multiplicity of microadenomas as compared to unsupplemented control diet. This study represents the first demonstration that naproxen can inhibit spontaneous colorectal adenomas in a controlled model system. The ability of naproxen to disrupt the formation of colorectal lesions early in the carcinogenesis process (microadenomas) provides strong support for its further development as a regimen for the chemoprevention of colorectal cancer in high-risk individuals. (Supported by NIH N01 CN-43309.) 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 LB-457. doi:10.1158/1538-7445.AM2011-LB-457