EVALUATION OF DOSE AND TREATMENT DURATION ON THE ESOPHAGEAL TUMORIGENICITY OF N-NITROSOMETHYLBENZYLAMINE IN RATS

N-Nitrosomethylbenzylamine (NMBA) is a potent esophagus-specific carci nogen that has been utilized extensively in the study of esophageal ca rcinogenesis in rats. While many studies have focused on the pathogene sis of NMBA-induced esophageal tumors, the tumorigenicity of NMBA itse lf has not been thoroughly investigated in any single, systematic dose -response study. Therefore, in this study we evaluated NMBA tumorigeni city in rats following various short-term s.c. treatment regimens with the aim of developing an abbreviated treatment protocol which could b e used in future studies. To assess the possible correlation of basal cell proliferation with NMBA tumorigenicity, we evaluated the expressi on of proliferating cell nuclear antigen (PCNA) in both control and NM BA-treated rats. In rats which received a cumulative NMBA dosage of 7. 5 mg/ kg over the course of 5 weeks, tumor incidence and multiplicity were as follows: 40% with 0.4 +/- 0.3 tumors/ rat at week 10; 100% wit h 2.2 +/- 1.0 tumors/rat at week 20; and 100% with 2.3 +/- 1.0 tumors/ rat at week 30. These rats exhibited marked increases in basal cell la beling, with indices that were 1.5- to 1.8-fold higher than controls. NMBA treatment regimens of shorter duration with equivalent or higher cumulative dosages were generally ineffective in producing esophageal tumors, even though significantly elevated levels of basal cell prolif eration occurred. Together, these findings indicate that the duration of NMBA treatment is of critical importance in the tumorigenic potenti al of the carcinogen.