Abstract LB-423: Combined chemopreventive effects of selective inducible nitric oxide synthase and cyclooxygenase-2 inhibitors on N-Nitrosomethylbenzylamine-induced rat esophageal tumorigenesis

Abstract

Abstract Esophageal cancer is the 6th most common cancer worldwide. Our laboratory has used a rodent preclinical model of esophageal squamous cell carcinoma to identify putative chemopreventive agents for this disease and to determine their mechanisms of action. In our previous studies, we found an association between increased expressions of the inducible nitric oxide synthase (iNOS) and of cyclooxygenase-2 (COX-2) in the development of N-Nitrosomethylbenzylamine (NMBA)-induced tumors in the rat esophagus. We also demonstrated that S, S’-1,4-phenylene-bis(1,2-ethanediyl) bis-isothiourea (PBIT), a selective iNOS inhibitor and celecoxib, a selective COX-2 inhibitor, significantly inhibited NMBA-induced rat esophageal tumorigenesis. In view of these observations, we initiated a study to determine the combination effects of low doses of celecoxib and PBIT on progression of preneoplastic lesions to papillomas in NMBA-treated rats. F344 rats were treated with NMBA (0.30 mg/kg b.w.) three times per week for 5 weeks. After 72 hours, animals were fed AIN-76A diet or AIN-76A diet containing different doses of celecoxib, PBIT, or celecoxib plus PBIT. At week 35, rats were sacrificed and esophageal tumors were counted. The incidence of esophageal tumors was decreased from 100% in NMBA-treated rats to 96.55%, 82.76% (P < 0.05) and 83.33% (P < 0.05) in rats treated with 300, 500 and 1000 ppm celecoxib, respectively. PBIT reduced the tumor incidence to 73.33% (P < 0.001) and 85.19% (P < 0.001) in rats treated with 50 and 100 ppm PBIT, respectively. The combination of celecoxib and PBIT reduced tumor incidence to 66.67% (celecoxib 300 ppm + PBIT 50 ppm; P < 0.001) and 71.43% (celecoxib 500 ppm + PBIT 50 ppm; P < 0.001), respectively. The tumor multiplicity was reduced in rats fed 300, 500 or 1000 ppm celecoxib to an average of 3.07 ± 2.20, 1.90 ± 1.40 (P < 0.05) and 2.00 ± 1.39 (P < 0.05) tumors per rat, respectively, compared with 4.73 ± 2.70 in rats fed the control diet. PBIT reduced the tumor multiplicity to 2.13 ± 1.80 (P < 0.05) and 1.89 ± 1.19 (P < 0.05) in rats fed 50 and 100 ppm PBIT, respectively. The combination of celecoxib and PBIT reduced the tumor multiplicity to 1.59 ± 1.37 (celecoxib 300 ppm + PBIT 50 ppm; P < 0.05) and 1.61 ± 1.42 (celecoxib 500 ppm + PBIT 50 ppm;P < 0.05), respectively. This study demonstrates, for the first time, that combination of low doses of selective iNOS and COX-2 inhibitors improves the efficacy of esophageal cancer prevention in preclinical animal model. The investigation of the cellular and molecular mechanisms of their actions is underway. Our study provided important information and rationale to develop a combination with agents that may have synergistic activity in human clinical trials of chemoprevention of esophageal cancer. (Supported by NIH/NCI RO1 CA131073-01A1). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-423.