Augmentation of Carcinogenesis by N-nitrosobis(2-oxopropyl)amine Administered During S Phase of the Cell Cycle in Regenerating Hamster Pancreas

Pancreatic acinar cells in various rodent species are capable of undergoing modulation to duct-like structures upon extended exposure to pancreatic carcinogens. Although the majority of malignant pancreatic neoplasms induced in rat and guinea pig are of acinar cell origin, some adenocarcinomas closely resembling those of ductal derivation have been reported. In hamster, on the other hand, carcinoma-induced duct-like modulation of acinar cells is followed exclusively by the development of ductal adenocarcinoma. The present experiments, in which the carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) was administered initially to hamsters during ethionine-induced pancreatic regeneration at a time when the maximum number of acinar cells was in S phase of the cell cycle, were undertaken to ascertain the extent and nature of acinar cell response to such treatment and the pattern of tumorigenesis. BOP was also administered weekly following the cessation of regeneration for periods ranging from 1.5 to 9 weeks to achieve total doses of 120, 90, and 40 mg of BOP per kg. Controls consisted of hamsters with normal nonregenerating pancreas that were treated with BOP on identical schedules to those of the experimental groups. The largest number of carcinomas (12 in 16 animals or 75%) developed in the highest-dose test group as compared to 10 in 26 animals or 38% in its control group. The difference was statistically significant (p less than 0.05). Other groups of hamsters with regenerating and nonregenerating pancreas receiving lower doses of carcinogen had tumor incidences which were not statistically different from one another. These experiments yielded ductal adenocarcinomas exclusively, although it is of interest that the two most common benign lesions encountered in these animals were cystadenomata often lined by zymogen-containing cells and duct-like modulation of acinar cells. Finally, in some of the animals with carcinomas, nests of duct-like structures, some of which appeared to arise from acini, were lined by severely atypical epithelium with numerous mitoses. The increased incidence and exclusive development of ductal adenocarcinoma in animals to whom carcinogen was administered during pancreatic regeneration coupled with the changes noted above are interpreted as presumptive evidence that acini may be involved in the pathogenesis of pancreatic ductal adenocarcinoma in the hamster.