MNNG-induced gastric carcinoma in ferrets infected with Helicobacter mustelae

Abstract

N-Methyl-N-nitro-N'-nitrosoguanidine (MNNG) is a gastric carcinogen in several animal species and has been used in a number of systems to dissect the co-carcinogenic potential of various compounds in the induction of gastric adeno-carcinoma. Recent epidemiological evidence suggests that Helicobacter pylori may play a role as a co-carcinogen in the etiology of this tumor in humans and we have been interested in developing an animal model to study this possibility. A related organism, H.mustelae, naturally colonizes the ferret stomach and causes persistent chronic gastritis. The pathology elicited by H.mustelae in ferrets has many similarities with the human disease including different stages of multifocal atrophic gastritis which underlie the gastric ulcer and gastric carcinoma syndrome. There is little evidence, however, demonstrating the susceptibility of ferrets toward chemical carcinogenesis. We have consequently undertaken a study to ascertain whether 10 6-month-old female ferrets given a single oral dose of MNNG (50–100 mg/kg) would develop adeno-carcinoma of the stomach. Five age-matched unmanipulated control animals were included for comparative purposes. All 15 ferrets were infected with H.mustelae. Nine of 10 ferrets dosed with MNNG developed gastric adenocarcinoma (29–55 months after dosing), while none of the five historical control ferrets examined an average of 63 months after the initiation of the study developed gastric tumors. By comparison, we have not observed gastric adenocarcinoma, nor has it been reported, in >10 years of observation of untreated ferrets naturally infected with H.mustelae. The H.mustelae-infected ferret, with demonstrated susceptibility to a gastric carcinogen, plus the recent availability of specific pathogen-free ferrets, should now allow longitudinal studies in vivo to probe the role of Helicobacter in the development of gastric cancer.