Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by JTE-522, a selective COX-2 inhibitor

Recent studies have demonstrated that overexpression of cyclooxygenase-2 (COX-2) and elevation of COX-2-mediated synthesis of prostaglandin E-2 (PGE(2)) were observed in various cancers including esophageal cancer, but their roles in carcinogenesis of the esophagi still remain unclear. To address the issue, we observed the reduction of N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in rat esophagi via JTE-522 (4-[4-cyclohexyl-2-methyl-oxazol-5-y1]-2-fluorobenzenesulfonamide), a selective COX-2 inhibitor. In this study, 54 F344 male rats were divided into nine groups; JTE-522 (3, 9 and 30 mg/kg) was administered orally. We also examined the effects of JTE-522 on COX-2 mRNA and synthesis of PGE2. In the group in which JTE-522 was administered intermittently at a daily dose of 30 mg/kg, the number of NMBA-induced esophageal tumors per rat significantly reduced, to 62% (P < 0.05), but the size of the tumors was not significantly inhibited. In the group in which JTE-522 was administered continuously five times weekly for 24 weeks at a daily dose of 9 mg/kg, both the number and size of tumors significantly reduced, to 29 and 44%, respectively (P < 0.05), Furthermore, JTE-522 suppressed not only tumor formation but also developing carcinomas (P < 0.0001). In this study, treatment with NMBA alone resulted in an <similar to>5-fold rise in expression of COX-2 mRNA detected by semi-quantitative RT-PCR analysis and an similar to7-fold increase in the production of PGE2 measured by ELISA compared with the normal esophageal mucosa, The up-regulated COX-2 expression did not decrease with the treatment of JTE-522 at the 3, 9 and 30 mg/kg doses; however, the increased levels of PGE2 synthesis were significantly decreased by administering JTE-522 (P < 0.01), Our study suggests that COX-2-mediated PGE2 is important in NMBA-induced esophageal tumorigenesis in rats, and therefore may be a promising chemotherapeutic target for the prevention and treatment of esophageal cancer, especially with selective COX-2 inhibitors.