The Mode of Action O F Methylcholanthrene on Cultures of Normal Tissues

The mode of action of carcinogenic agents is one of the most fundamental problems of cancer research. Available evidence clearly indicates that the potentiality of malignant transformation of any normal cell type is determined, in part at least, by hereditary factors. I t would seem reasonable, therefore, for the study of the mode of action of carcinogens, to select cell types possessing a favorable hereditary constitution and to subject these cells to the influence of suitable carcinogenic agents under controlled conditions. The present report deals primarily with a systematic investigation of the action of methylcholanthrene on cultures of subcutaneous tissue of albino rats and on cultures derived from the ventral musculature of mice of the C,,H strain. Methylcholanthrene was chosen because it is one of the most potent chemical carcinogenic agents known and can be secured in a state of the highest purity. A single experiment was done with 1 : 2 : 5 : 6-dibenzanthracene. Work which will be discussed in a subsequent paper has demonstrated that the subcutaneous injection of a lard solution of methylcholanthrene or of dibenzanthracene gives rise to sarcomas at the site of injection in practically all rats of the strains used for our tissue cultures. In a comparative study of eight inbred strains of mice, Andervont (1) found that C,,H mice have the highest susceptibility to the development of subcutaneous sarcomas following the injection of these hydrocarbons subcutaneously. Assuming, therefore, that these sarcoma cells are derived from cells of the fibroblast type, it appears that the cultures chosen for this study have an hereditary constitution favorable for carcinogenesis. The study of the mode of action of carcinogenic agents by means of tissue cultures has certain obvious advantages over similar studies using living animals. Thus it is possible to control two factors which are generally recognized as important in pharmacological research, namely, the concentration of the compound and the time during which the compound exerts its influence on the biological object under investigation. Furthermore, any pronounced deviation from the normal rate of cell proliferation can readily be determined in tissue cultures. Cytological examinations, moreover, reveal finer changes in morphology. On the other hand, the tissue culture technic has its limitations, since the conditions in the cultures are not identical with those of the same tissues in s i b . This is particularly true of any systemic action exerted