IV CARCINOGENIC CHEMICALS 86l 



to be involved. The mechanism of carcinogenesis following entrance of the 

 carcinogen into the cell is still unknown. There is evidence that there is "binding" 

 of the carcinogen by cellular protein. (Wiest and Heidelberger, 1953a, b, c), similar 

 to the "binding" of butter yellow by liver cells during hepatic carcinogenesis 

 (Miller and Miller, 1947). These findings have been interpreted as being of 

 probable significance in elucidating the "enzyme deletion" hypothesis of Potter 

 (1944). 



Crabtree (1946) has demonstrated that "anticarcinogens" (chemicals which 

 inhibit carcinogenesis induced by polycyclic hydrocarbons) react with — SH 

 groups which are present in cellular constituents {e.g. sulphur containing 

 amino acids). These agents (anticarcinogens) which block carcinogenesis are 

 excreted as mercapturic acids and deplete the svdphur content of the target tissue. 

 The inhibitors probably combine preferentially with — SH groups. Although 

 they probably react with — SH groups, the carcinogens are not excreted as 

 mercapturates. 



Species factors, as well as genetic factors within the species, are important in 

 determining the carcinogenic action of the polycyclic hydrocarbons (Wolf, 1952). 

 In the case of mouse pulmonary (Shimkin, 1955) and mammary tumors (Kirsch- 

 baum and Liebelt, unpublished) there is positive correlation between susceptibility 

 to the spontaneous disease and induction by polycyclic carcinogenic hydrocarbons. 

 This suggests that the cancer-inducing agents may augment a "spontaneous" 

 process and that the same genes responsible for susceptibility to the spontaneous 

 neoplasm also control the response to these tumor-inciting chemicals. Heston 

 ( 1 95 1 ) believes that of the multiple factors involved in the genesis of mouse neo- 

 plasms, some may be deleted with carcinogenesis still occurring if others are 

 sufficiently potent. 



For mouse leukemia, however, high susceptibility to one leukemogenic agent 

 {e.g., X-rays or estrogenic hormone in CBA mice) does not imply a similar degree 

 of susceptibility to the hydrocarbons (Kirschbaum and Mixer, 1947). The car- 

 cinogenic hydrocarbons may, however, be highly leukemogenic for other strains 

 of mice {e.g., the Dba/2) (Mider and Morton, 1939). The C57BL strain is ex- 

 tremely susceptible to the leukemia (thymoma)-inciting action of X-rays (Kaplan, 

 1947), but resistant to the induction of leukemia by either estrogenic hormone or 

 methylcholanthrene (Kirschbaum and Mixer, 1947). 



Studies of the metabolites of the polycyclic hydrocarbons have yielded little 

 information which might elucidate the mechanism of carcinogenesis. It has been 

 suggested (Greenstein, 1954) that new experimental biochemical approaches 

 involving the interaction of carcinogens with tissue components might be of great 

 value. 



{b) Azo dyes 



The azo dyes induce liver tumors althovigh administered at extrahepatic sites. 

 For example, oral ingestion of 4-dimethylaminoazobenzene with the appropriate 

 diet may be carcinogenic for the liver (Kinosita, 1940). Related compounds 

 {e.g. o-aminoazotoluene) have also been demonstrated to be hepatic carcinogens 

 (Andervont and Dunn, 1947). The riboflavin content of the liver is an important 



Literature p. 8yo 



