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

Abstract

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...

Spectral Markers in Preneoplastic Intestinal Mucosa: An Accurate Predictor of Tumor Risk in the MIN Mouse

“…The light scattering fingerprints obtained from the distal small bowels of MIN and control mice revealed dramatic qualitative differences as indicated by changes in backscatter intensity (different colors) in the small intestine but not the colon. This finding accurately reflects the future occurrence of neoplasia in this model in that >90% of adenomas are located in the small bowel with minimal tumorigenesis in the colon (17,18). Indeed, these data suggest that light scattering abnormalities predict a genetic substrate to neoplastic transformation before occurrence of neoplasia.…”

Celecoxib Treatment Alters the Gene Expression Profile of Normal Colonic Mucosa

“…ACFs are considered to be an early preneoplastic lesion in the colon (75), and the ability to decrease the frequency of ACF after carcinogen treatment is used routinely in experimental models of colon cancer to estimate the cancer preventive effect of different agents (76). It is particularly well established that NSAIDs (77)(78)(79) and celecoxib (80)(81)(82)(83) decrease the frequency of carcinogen-induced ACFs in the colon in animal models. It has also been shown that the number of ACF in patients who received sulindac sulfide is decreased (84).…”

Alteration of Gene Expression in Normal-Appearing Colon Mucosa of APC min Mice and Human Cancer Patients

“…Because we did not examine this tissue under a microscope, we cannot rule out the possibility that it contained microscopic lesions such as ACF, which may have altered expression of certain genes (22). However, previous studies have reported that there are relatively few ACF in the colon of APC min mice (23,24).…”