title: ECL-cell derived gastric cancer in male cotton rats dosed with the H2-blocker loxtidine.
abstract: Spontaneously hypergastrinemic cotton rats (Sigmodon hispidus) develop tumors that have the phenotype of an adenocarcinoma but most likely originate from the enterochromaffin-like (ECL) cells. Among inbred animals approximately 50% of the females, but <1% of males develop spontaneous gastric carcinomas. Gastrin is the principle carcinogen in this model, as >4 months of hypergastrinemia results in carcinoma, but a gastrin receptor antagonist prevents carcinomas. Carcinomas can also be induced by partial corpectomy. In the present study, the insurmountable H2-receptor antagonist loxtidine (200 mg/kg/day) was given to male cotton rats for 6 months. The loxtidine-dosed animals developed hypergastrinemia, whereas control animals remained normogastrinemic. At termination, 4 of 5 cotton rats had cancer located to the oxyntic mucosa, whereas 1 animal had dysplasia. The gastric mucosa of all of the control animals was normal. In the dysplastic mucosa of loxtidine-dosed animals there was a marked increase in chromogranin A-positive cells, where numerous groups of cells also stained positive with the Sevier-Munger technique. In areas of high proliferation and cancer there were also histidine decarboxylase, chromogranin A, and Sevier-Munger-positive cells, altogether indicating an ECL cell origin of the tumors. This represents an interesting animal model where ECL cell-derived gastric cancer can be induced by pharmacological acid inhibition in 6 months.
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway. reidar.fossmark@medisin.ntnu.no
authors.forename: Reidar
authors.initials: R
authors.lastname: Fossmark
authors.forename: Tom C
authors.initials: TC
authors.lastname: Martinsen
authors.forename: Karin E
authors.initials: KE
authors.lastname: Bakkelund
authors.forename: Shiro
authors.initials: S
authors.lastname: Kawase
authors.forename: Helge L
authors.initials: HL
authors.lastname: Waldum
mesh_terms: D000818:Animals; D019861:Enterochromaffin-like Cells / Q000187:drug effects / Q000473:pathology*; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005755:Gastrins / Q000097:blood; D006635:Histamine H2 Antagonists / Q000633:toxicity*; D007150:Immunohistochemistry; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D016205:Sigmodontinae; D013270:Stomach / Q000033:anatomy & histology / Q000187:drug effects; D013274:Stomach Neoplasms / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D014230:Triazoles / Q000633:toxicity*
chemical_list: D005755:Gastrins; D006635:Histamine H2 Antagonists; D014230:Triazoles; C039993:loxtidine