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.