Effects of Delays in the Cell Cycle on the Induction of Preneoplastic and Neoplastic Lesions in Rat Liver by 1,2-Dimethylhydrazine1

recently, it has been shown that cell proliferation is essential for the induction of very early focal lesions in the liver during initiation (2, 3, 35, 38, 39). However, the precise role of cell proliferation in the initiation process is not clear. A common hypothesis visualizes its predominant role as stimulating DNA replication which somehow †̃ †̃fixes' †̃ permanently one or more biochemical lesions in DNA in the daughter strands (4, 25). Utilizing one biological model for the sequential analysis of liver carcinogenesis (2, 31), we showed previously that i ,2DMH, a colon carcinogen, could induce presumptive preneo plastic foci of altered cells in rat liver only when coupled with a cell-proliferative stimulus such as PH (35, 38). To further elucidate the role of cell proliferation in hepatocarcinogenesis, the present study was conducted to investigate whether 2 different types of delays in the cell cycle would influence the induction of hepatic preneoplasia and neoplasia by 1,2-DMH in a similar fashion. In designing the initial experiments, use was made of class ical inhibitors of DNA synthesis, such as hydroxyurea. Attempts to use this approach were unsuccessful, because of the early death of the animals. Resort was then made to the use of HC. This compound, an effective inhibitor of DNA synthesis (27), was successfully used recently in a study using a single dose of MNU as the carcinogen and livercancer appearance as the end point (16). With this approach, the progression through the cell cycle was delayed by administration of HC during G1 after the injection of 1,2-DMH in association with PH, and the effect of this treatment on the genesis of very early presumptive preneoplastic foci of resistant hepatocytes was measured. In addition, the effect of delaying the time of performance of PH after the administration of the carcinogen on the induction of presumptive preneoplastic and neoplastic lesions was ob served. The results of these experiments are the subject of this paper.