Oncogenesis, mutagenesis, DNA damage, and cytotoxicity in cultured mammalian cells treated with alkylating agents.

esis. One is to trace step by step the process of oncogenic transformation in cells assembled from components, DNA, chromatin, nuclei, and cytoplasm, that have been treated with carcinogens under carefully controlled conditions in vitro ; the other approach is to establish uniform associa tions between the process of oncogenic transformation and other processes that are better understood at the molecular level. We have chosen the latter approach for the studies on the effects of monofunctional methylating and ethylating agents reported in this series of papers. A prerequisite for our approach is that the processes that we study should have end points that can be measured accurately and interpreted with a minimum of ambiguity. For the process of mutation, colonies of AZG3-resistant cells, and for the process of alkali-labile DNA damage, changes in the molecular weight of DNA on alkaline sucrose gradients have been shown to fulfill most of the criteria for accuracy (3, 8, 19, 22, 24, 32, 33).4 Some difficulties remain in the interpretation of the data of mutation and DNA damage, but experiments are designed to resolve those difficulties in the course of this work. In the present study, we report associations between mutations to AZG resistance, cytotoxicity, and alkali-labile DNAdamage. Mutation to AZG resistance,which could not be detected in the tetnaploid C3H/10T1/2 cells, was mea sured in diploid Chinese hamster V79 cells to be related through associations with DNA damage and cytotoxicity to the effects of the alkylating agents in the transformable cells. Preliminary accounts of this work have been pub lished (21).