Carcinogenic doses of methylnitrosourea induce dose response related delay in transit through S and G2 phases in mouse epidermis: a cell kinetic study.

Abstract

The cell kinetic, tumorigenic and carcinogenic effects of the short acting, alkylating carcinogen N-methyl-N-nitrosourea (MNU) on hairless mouse epidermis were investigated. The epidermal mitotic rate, the mitotic index, and the number of basal and suprabasal cells were scored in histological sections. Incorporation of [3H]thymidine and flow cytometric analysis of cellular DNA and protein content were performed on isolated basal cells at intervals for up to 10 days after a single application of either 1 or 10 mg MNU. The ensuing tumor rates and yields were observed for up to 48 weeks after 1 mg MNU and 30 weeks after 10 mg MNU. Generally, MNU induced an initial delay in epidermal cell cycle progression with an accumulation of cells in the S and G2 phases. Some days after treatment the delayed cells were released and entered mitosis. One milligram MNU caused a moderate delay of cells in S and G2, lasting for 2-3 days, and this was followed by a release leading to an increased number of suprabasal cells on day 7. The highest dose of MNU caused a more pronounced delay in transit through S and G2 and seemed to be followed by rapid regenerative proliferation. The subsequent tumor crop after 10 mg was significantly higher than that seen after the lowest dose. The present cell kinetic results are consistent with previous data from the study of other carcinogens, all showing a carcinogen-induced initial reduction in DNA synthesis after appropriate doses. A delay in transit through G2 phase was found as well, indicating that a general delay in cell cycle progression may follow the application of most (or all) carcinogens.