Chemopreventive effect of N-(2-cyclohexyloxy-4-nitrophenyl)methane sulfonamide (NS-398), a selective cyclooxygenase-2 inhibitor, in rat colon carcinogenesis induced by azoxymethane.

Abstract

Non‐steroidal anti‐inflammatory drugs (NSAIDs) such as sulindac and indomethacin inhibit colon carcinogenesis, and selective cyclooxygenase (COX)‐2 inhibitors are considered to be potential chemopreventive agents without the side effects of usual NSAIDs. We reported that NS‐398, N‐(2‐cyclohexyloxy‐4‐nitrophenyl)methane sulfonamide, suppressed the formation of preneoplastic lesions, aberrant crypt foci (ACF), induced by azoxymethane (AOM) in a short‐term assay of rat colon carcinogenesis. In this study, we examined the effects of long‐term NS‐398 administration on rat colon carcinogenesis. After three AOM treatments at weekly intervals, a dose of 10 mg/kg of NS‐398 in 5% Arabic gum solution was administered by gavage three times per week in group 2 until the termination of the experiment. Rats in group 1 were fed in a basal diet and given 5% Arabic gum solution alone after AOM treatment. At 40 weeks after the first AOM treatment, all rats were killed and the whole intestines including colon were examined. While the incidences of whole intestinal and colon neoplasms in group 1 were 84.6% and 80.8%, respectively, those in group 2 (given NS‐398) were 51.9% and 44.4% respectively (P=0.0177 and P=0.0103 by Fisher's exact test, respectively). The multiplicities in group 2 (0.67 ± 0.78 and 0.48 ± 0.58) were also decreased significantly compared with those (1.39 ± 1.10 and 1.08 ± 0.74) in group 1 (P < 0.01 by Welch's method and P < 0.002 by Student's t test, respectively). In immunohistochemistry for proliferative cell nuclear antigen (PCNA), the PCNA‐stained cell index (7.40 ± 0.5) in group 2 was significantly decreased from that in group 1 (14.03 ± 0.82) (P < 0.001 by Welch's method). The results suggest that NS‐398, a selective COX inhibitor, has a chemopreventive activity against colon carcinogenesis without side‐effects such as gastric ulceration.