ESTABLISHMENT OF THE OPTIMUM CONDITIONS FOR INDUCTION OF STOMACH CARCINOMA IN RATS BY CONTINUOUS ORAL ADMINISTRATION OF N-METHYL-N-NITROSOUREA

Abstract

The optimum condition for gastric carcinomas to be induced by N-methyl-N-nitrosourea (MNU) selectively in the glandular portions of the rat stomach was investigated. MNU in drinking water at various dose levels with shielding from light was administered ad libitum to a group of inbred male F344 rats for 15 weeks and thereafter switched to tap water to maintain them for further 25 weeks. The rats received MNU at the concentration of more than 200 ppm resulted in high mortality because of chronic toxicity by 25 weeks after withdrawal of MNU. Administration of MNU at 100 ppm followed by at least 25-week maintenance without the compound was concluded to be the optimal condition for a rat new model of gastric carcinogenesis, because the experiment under such a condition yielded a high incidence (95.2%) of carcinomas in the glandular stomach with no death at the end of the experiment. Almost all neoplastic lesions occurred in the pyloric regions; well differentiated adenocarcinoma with submucosal invasion accounted for approximately 50% of all the neoplastic lesions. Cell kinetics analysis using BrdU-immunohistochemical technique during MNU administration revealed 2-fold increase of DNA-synthesizing cells at 3 weeks after the start of administration as compared to the controls of normal stomach. These BrdU-positive cells, however, gradually decreased in number with time, approximating to the control value by 15 weeks. The results may indicate some suppressive effect of lengthy treatment of MNU on the growth of MNU-initiated atypical epithelium of the stomach.