Large bowel carcinogenesis in mice and rats by several intrarectal doses of methylnitrosourea and negative effect of nitrite plus methylurea

Abstract

The carcinogenic effect of several dose levels and regimens of an aqueous solution of N-methyl-N-nitrosourea (MNU) administered intrarectally to mice and rats is reported. In Ha/ICR Swiss mice, a single dose of 1.8 mg MNU induces mainly lymphomas and pulmonary tumors in less than 20 weeks. Repeated doses of 1.5 mg MNU induces lymphomas, pulmonary tumors, and also large bowel tumors in less than 20 weeks. Doses of 0.3 mg decreased the yield of lymphomas and increased large bowel neoplasms over a period of 40 to 60 weeks. Repeated doses of 0.06 mg also gave a low yield of lymphomas and large bowel tumors over a 60-week period. Thus, a maximal yield of lymphomas is seen with a brief regimen of high doses, whereas large bowel tumors occur with a more frequent lower dose rate. Male Fischer strain rats given 1.0 or 2.5 mg MNU 3 times a week for 10 weeks had a multiplicity of large bowel tumors, proportional to dose, in 25 to 30 weeks. In fact, the high dose level led to a 100% yield in less than 20 weeks. Lymphomas were seen only at the higher dose when the animals were were young, at the beginning of the test. In mice and rats the carcinomas were polypoid or plaque shaped and were well differentiated with extensive invasion but no metastases. The adenomas were pedunculated or sessile. Intrarectal administration of a mixture of methylurea and nitrite for 20 weeks and further observation of the rats for an additional 35 weeks yielded no colon tumors. Thus, there is indirect evidence of a lack of the in situ formation of carcinogenic MNU in the large bowel under physiological conditions.