Use of non-steroidal anti-inflammatory drugs (NSAIDs) for chemoprevention of colon cancer has been hindered by their potential gastro-intestinal toxicity. Nabumetone, which is approximately 10 to 36 times safer than conventional NSAIDs, was evaluated in 2 models of experimental colon carcinogenesis. In azoxymethane (AOM)-treated Fisher 344 rats, nabumetone caused dose-dependent inhibition of aberrant crypt foci (ACF), with 750 and 1,500 ppm resulting 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 approximately half of the intestinal tumors. Interestingly, inhibition of intermediate biomarkers in both models was markedly greater in the distal than the proximal bowel. To mechanistically evaluate this regional selectivity, we assessed cyclo-oxygenase-2 (COX-2) expression in the uninvolved mucosa and demonstrated a 3-to 4-fold excess in the distal relative to the proximal bowel in both MIN mice and AOM-treated rats. We then investigated another putative NSAID target, peroxisome proliferator-activated receptor-␦ (PPAR-␦) and demonstrated up-regulation during AOM-induced colonic tumorigenesis. Furthermore, in pre-neoplastic mucosa, there was a 3-fold excess of PPAR-␦ in the distal colon. We demonstrate that nabumetone is an effective protective agent in both experimental models of colon carcinogenesis. The striking distal predilection of nabumetone may be, at least partially, explained by distal bowel over-expression of COX-2 and PPAR-␦. © 2001 Wiley-Liss, Inc.Key words: non-steroidal anti-inflammatory drugs; chemoprevention; colon cancer; nabumetone; azoxymethane Despite significant medical advances in diagnosis and therapy, colorectal malignancies remain the second leading cause of cancer mortality in the United States, 1 underscoring the need for effective chemopreventive strategies. A variety of agents have been purported to protect against colon cancer; of these, the non-steroidal anti-inflammatory drugs (NSAIDs) have demonstrated the greatest promise. 2 The epidemiological and experimental evidence indicates that NSAIDs can reduce the risk of colorectal cancer by up to 50%; 3 however, utilization of NSAIDs for colon-cancer prevention has been hindered by their propensity to cause gastro-intestinal injury. 4 To minimize these untoward effects, novel NSAIDs have been developed with selectivity for cyclo-oxygenase-2 (COX-2), the COX isoform not expressed in normal gastro-intestinal epithelium. 5 COX-2, but not COX-1, is markedly up-regulated early during colon carcinogenesis. 3 Therefore, selective targeting of COX-2 may afford protection against colorectal cancer without the gastro-intestinal toxicity associated with depletion of COX-1-dependent mucosal cytoprotective prostaglandins.Nabumetone, an NSAID in widespread clinical use, has a 7-fold higher affinity for COX-2 than COX-1. 6 Moreover, a meta-analysis indicates that nabumetone is 10 to 36 times s...