ECL-cell derived gastric cancer in male cotton rats dosed with the H2-blocker loxtidine

• Published in: Cancer research (Chicago, Ill.) Vol. 64; no. 10; pp. 3687 - 3693
• Main Authors: FOSSMARK, Reidar, MARTINSEN, Tom C, BAKKELUND, Karin E, KAWASE, Shiro, WALDUM, Helge L
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.05.2004
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Enterochromaffin-like Cells - drug effects; Enterochromaffin-like Cells - pathology; Female; Gastric Mucosa - drug effects; Gastric Mucosa - pathology; Gastric Mucosa - secretion; Gastrins - blood; Histamine H2 Antagonists - toxicity; Immunohistochemistry; Male; Medical sciences; Organ Size - drug effects; Pharmacology. Drug treatments; Rats; Sigmodontinae; Stomach - anatomy & histology; Stomach - drug effects; Stomach Neoplasms - blood; Stomach Neoplasms - chemically induced; Stomach Neoplasms - pathology; Triazoles - toxicity; Tumors; Vertebrata; Mammalia; Rat; Animal; Rodentia; Digestive diseases; Male; Malignant tumor; Antihistaminic; Stomach cancer; H2 Histamine receptor; Gastric disease
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-03-3647

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.