Evaluation of combination effects of three carcinogens at low dose: Initiation of pancreatic ductal carcinogenesis in a Syrian hamster rapid production model.

Abstract

Combination effects of low doses of three carcinogens, N-nitrosobis (2-oxopropyl) amine (BOP), N-methyl-N-nitrosourea (MNU), and diethylnitrosamine (DEN) on initiation of pancreatic ductal carcinogenesis were examined using a rapid production model in female Syrian hamsters. Groups of animals received intraperitoneal injections of BOP, MNU, and DEN at doses of 20, 10, and 20mg/kg body weight, respectively, either alone or in combination as initiators, followed by three cycles of augmentation pressure, established earlier to cause selective growth of initiated cell populations. All hamsters were sacrificed 10 weeks after the commencement and pancreatic duct lesions were histopath-ologically diagnosed. The low single dose of 20mg/kg body weight of BOP still retained relatively strong initiating activity resulting in substantial induction of ductal adenocarcinomas 67%, while neither MNU nor DEN alone exerted significant initiating activity under the present experimental conditions. Combined administration of these three carcinogens either simultaneously or serially at intervals of one day exhibited no significant synergism, with the incidences and mean numbers of ductal lesions being almost the same as those of the BOP alone group. Thus, under the present experimental conditions, BOP, MNU, and DEN exerted no synergism regarding initiation of pancreatic ductal carcinogenesis in hamsters.