Interrelationships between cellular proliferation, DNA alkylation and age as determinants of ethylnitrosourea-induced neoplasia.

Thirty-day-old Sprague--Dawley rats were used to study the persistence of DNA lesions (e.g., O6-alkylguanine) induced by various doses of ethylnitrosourea (ENU). Cellular proliferation was measured as an increment of DNA content per organ at 7 days post-treatment. We observed that the persistence of O6-EtGua was not affected by the various dose levels. Comparing the 3 organs, the persistence of O6-EtGua ranked in the order of brain greater than kidney greater than liver, while the percent increase in DNA content was measured as liver greater than kidney greater than brain. When the target specificity of ENU carcinogenesis in 30-day-old rats was compared to that following transplacental exposure in terms of its relationship to the persistence of DNA lesions and the rate of target cellular proliferation, it permitted the conclusion that induction of neoplasia in target cells is not only determined by persistent DNA lesions but also by the rate of proliferation of target cells at the time of exposure.