On the Mechanism of Action of Carcinogenic Substances*

In the study of cancer one of the central problems is the elucidation of the pathogenesis of malignant tumors. The direction taken by such studies varies in accordance with prevailing points of view on the etiology of cancer. Since the discovery of carcinogenic compounds by Cook, Kennaway, and others ( i , 7), the theory of a chemical etiology of malignant tumors has been advanced. According to this theory the socalled "spontaneous" tumors, which include the majority of the tumors of man, and which are of the greatest interest for practical medicine, develop as the result of the action of endogenous carcinogenic substances engendered in the organism. Recently the hypothesis of endogenous carcinogenic substances has been strengthened by the results of the investigations of Schabad (44, 45), Hieger (17), des Ligneris (9, lO), Steiner (47), and Kleinenberg et al. ( I 9 ) . A tendency exists also, as indicated by the work of Roffo (43), to invoke a chemical explanation for the carcinogenic action of certain physical factors, such as ultraviolet rays. There is reason to believe that certain endogenous carcinogenic substances may prove to be closely related to some of the known synthetic carcinogenic hydrocarbons. If the theory of the chemical etiology of malignant tumors be accepted as a working hypothesis, one of the first questions to arise concerns the mechanism of action of carcinogenic substances. What is their mode of action? In what way do these substances affect normal cells to transform them into tumor cells ? Problems of the mechanism of the action of carcinogenic substances have been of particular interest to these laboratories in recent years. The purpose of this communication is to present and discuss the results of some of the studies in this field which I have conducted in association with collaborators.'