CA: A Cancer Journal for Clinicians, Vol 31, 241-253, Copyright
© 1981 by American Cancer Society
The Mechanism of Carcinogenesis: A Study of the Significance of Cocarcinogenic Action and Related Phenomena
I. Berenblum M.D.
The effect of croton resin on carcinogenesis was studied under varying conditions, in order to determine the nature of cocarcinogenic action (the augmentation of carcinogenesis that occurs when croton resin is applied to the skin concurrently with a dilute solution of 3,4-benzpyrene) and its relation to the process of carcinogenesis.
No cocarcinogenic effect was observed when the croton resin was applied to the skin and the benzpyrene was injected at a distance (intraperitoneally); nor was it possible to augment the carcinogenic effect of benzpyrene on subcutaneous tissues, by injection of croton resin together with the benzpyrene.
While augmentation of carcinogenesis was very pronounced when croton resin was applied to the skin concurrently with a dilute solution of a potent carcinogen (3,4-benzpyrene), none was observed with concentrated solutions of different carcinogens, irrespective of whether their potency was high (3,4-benzpyrene), moderate, (1,2,5,6-dibenzanthracene), or very low (1 ,2-benzanthracene).
Preliminary treatment with croton resin for a period of 26 weeks failed to influence significantly the response of the mouse's skin to subsequent applications of benzpyrene. On the other hand, croton resin applied to the skin subsequent to a limited period of benzpyrene treatment led to a striking increase in tumor development.
Croton resin applied to papillomas already established appeared to facilitate their conversion to malignancy.
From consideration of these results, the suggestion is put forward that the three phases of carcinogenesis—(a) the development of the preneoplastic phase (latent period), or precarcinogenic action; (b) the conversion of this into the wart stage, or epicarcinogenic action; and (c) the malignant transformation of these warts, or metacarcinogenic action—are probably not simply stages of one single carcinogenic process, but independent processes. The carcinogenic hydrocarbons possess all three actions; croton resin possesses only the second and third, and cannot, therefore, produce tumors by itself.
No precise knowledge is yet available as to the nature of cocarcinogenic action, but two possible modes of action are discussed.
Attention is also drawn to the clinical implications of the existence of cocarcinogenic, epicarcinogenic, and metacarcinogenic actions on the part of noncarcinogenic agents in humans.
