Granuloma pouch assay. III. Enhancement of the carcinogenic effect of N-methyl-N'-nitro-N-nitrosoguanidine.

Proliferation of granulation tissue on the inside of a subcutaneous (s.c.) air pocket was induced in rats by administration of 0.5 ml of 0.25% croton oil (granuloma pouch). Two days after induction of the granuloma, i.e., during the period of maximal cell growth, a single dose of 0.6 mg or 0.1 mg N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was administered into the pouch. Fibrosarcomas of various histopathological types developed in 87% of the rats receiving the high dose and in 64% of the low dose animals. The mean latency period was 47.5 and 51.7 weeks respectively. Only one local sarcoma developed in rats treated with 0.6 mg MNNG by the s.c. route, and no tumors were observed in the groups treated with 0.1 mg s.c. The appearance of local sarcomas in the granuloma pouch tissue is correlated with previously reported frequency of point mutations (OUAR and HGPRT-) induced in granuloma fibroblasts with the same doses of MNNG. Possible mechanisms explaining the marked enhancement of the carcinogenic effect of MNNG in the granuloma pouch assay are discussed.