Carcinogenesis, Vol. 22, No. 4, 547-551,
April 2001
© 2001 Oxford University Press
ACCELERATED PAPER |
Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by JTE-522, a selective COX-2 inhibitor
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, 54-Shogoin Kawahra-cho, Sakyoku Kyoto 606-8507, Japan
Recent studies have demonstrated that overexpression of cyclooxygenase-2 (COX-2) and elevation of COX-2-mediated synthesis of prostaglandin E2 (PGE2) 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-methyloxazol-5-yl]-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 ~5-fold rise in expression of COX-2 mRNA detected by semi-quantitative RT–PCR analysis and an ~7-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.
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