ENHANCEMENT OF INDUCTION OF INTESTINAL ADENOCARCINOMAS BY CYCLOSPORINE IN RATS GIVEN A SINGLES DOSE OF N-METHYL N-NITROSOUREA

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Abstract
Dietary administration of cyclosporine (CsA) to rats induces lymphoproliferative disorders involving the gut lymphoid plaques with frequent mucosal ulceration. In this study, we investigated whether administration of a known chemical carcinogen prior to CsA treatment modifies the development of the lesions induced by CsA. Male Sprague-Dawley rats were given either a single i.p. injection of N-methyl N-nitrosourea (MNU) (25 mg/kg) or the solvent-and one week thereafter they were fed on a diet containing 0.011% CsA. Control rats were fed a basal diet with or without prior MNU treatment. Of the rats that received MNU and CsA, 60% developed adenocarcinomas of the small and large intestine arising in the regions of the intestinal lymphoid plaques. Only 1 of 12 rats given MNU followed by a basal diet developed adenocarcinoma. No tumors developed in rats treated with CsA alone, but there was atypical proliferation of the intestinal mucosa in conjunction with lymphoid hyperplasia of the gut. The mucosal damage secondary to CsA-induced lymphoid lesions probably acted as a promoting stimulus for the development of intestinal carcinomas.