Distal bowel selectivity in the chemoprevention of experimental colon carcinogenesis by the non-steroidal anti-inflammatory drug nabumetone

Use of non-steroidal anti-inflammatory drugs (NSAIDs) for chemoprevention o f colon cancer has been hindered by their potential gastro-intestinal toxic ity. Nabumetone, which is approximately 10 to 36 times safer than conventio nal NSAIDs, was evaluated in 2 models of experimental colon carcinogenesis. In azoxymethane (AOM)-treated Fisher 344 rats, nabumetone caused dose-depe ndent inhibition of aberrant crypt foci (ACF), with 750 and 1,500 ppm resul ting in 15% and 37% reductions, respectively (p < 0.05). Moreover, complex ACF were reduced by 48% in the latter group. MIN mice studies confirmed the chemopreventive efficacy of nabumetone, with 900 ppm suppressing approxima tely half of the intestinal tumors, Interestingly, inhibition of intermedia te biomarkers in both models was markedly greater in the distal than the pr oximal bower. To mechanistically evaluate this regional selectivity, we ass essed cyclo-oxygenase-2 (COX-2) expression in the uninvolved mucosa and dem onstrated a 3- to 4-fold excess in the distal relative to the proximal bowe l in both MIN mice and AOM-treated rats. We then investigated another putat ive NSAID target, peroxisome proliferator-activated receptor-delta (PPAR-de lta) and demonstrated up-regulation during AOM-induced colonic tumorigenesi s. Furthermore, in pre-neoplastic mucosa, there was a 3-fold excess of PPAR -delta in the distal colon. We demonstrate that nabumetone is an effective protective agent in both experimental models of colon carcinogenesis. The s triking distal predilection of nabumetone may be, at least partially, expla ined by distal bowel over-expression of COX-2 and PPAR-delta. (C) 2001 Wile y-Liss, Inc.