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 ϳ50% 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.

Achlorhydria, Parietal Cell Hyperplasia, and Multiple Gastric Carcinoids: A New Disorder?

“…7 Long-term overstimulation of parietal cells may lead to parietal cell degeneration as shown in transgenic hypergastrinemic mice, 8 and spontaneously in a proportion of female cotton rats. 4 These cotton rats have a condition very similar to that described in the case report by Abraham and coworkers.…”

Treatment of gastric carcinoids type 1 with the gastrin receptor antagonist netazepide (YF476) results in regression of tumours and normalisation of serum chromogranin A

“…32,33 There is also extensive evidence that hypergastrinaemia is pivotal in the development of ECL cell-derived gastric neoplasia. In animal models of hypergastrinaemia and gastric carcinogenesis, rats, 34,35 41,42 develop either ECL cell carcinoids, adenocarcinomas in the oxyntic mucosa or both. Animals with hypergastrinaemia have an increased risk of developing ECL cell carcinoids accompanied by either increased or decreased gastric acidity.…”

Long-Term Serotonin Administration Induces Heart Valve Disease in Rats

“…Immunohistochemical staining for proliferating cells was performed with the monoclonal antibody Ki-67, MIB-5 (code M7248, Dako), as described. 26 …”