Suppression of Occurrence and Advancement of β-Catenin-accumulated Crypts, Possible Premalignant Lesions of Colon Cancer, by Selective Cyclooxygenase-2 Inhibitor, Celecoxib

Suppression of occurrence and advancement of premalignant lesions is important for cancer prevention. Our previous studies clarified that β-catenin-accumulated crypts, independent of aberrant crypt foci (ACF), are probably direct precursors of colon cancers in rats. Here we investigated the effects of a selective cyclooxygenase-2 inhibitor, celecoxib, on the development of β-catenin-accumulated crypts in comparison with those on ACF. Male F344 rats were divided into 4 groups. Groups 1-3 were administered azoxymethane (AOM) s.c. at a dose of 15 mg/kg body weight, once weekly for 3 weeks to induce β-catenin-accumulated crypts. Groups 2 and 3 also received experimental diet containing celecoxib (500 and 1500 ppm, respectively) for 8 weeks, starting a week before the first dosing of AOM. At termination, the frequency and crypt multiplicity (number of crypts/lesion) of β-catenin-accumulated crypts of groups 2 and 3 were significantly less than that of group 1. Furthermore, numbers of silver-stained nucleolar organizer regions (AgNORs)/nucleus in β-catenin-accumulated crypts were also decreased by exposure to celecoxib. In this study, celecoxib had greater effects on the frequency and growth of β-catenin-accumulated crypts than on those of ACF. These findings represent additional evidence that β-catenin-accumulated crypts are premalignant lesions of colon cancer. The results also suggest that β-catenin-accumulated crypts could be a novel target for evaluation of possible chemopreventive agents against colon carcino-genesis, and indicate that possible chemopreventive effects of celecoxib on the initial stage of colon carcinogenesis may be related to modulation of cell proliferation activity in such early lesions.