Effects of an inducer and an inhibitor of hepatic metabolism on the antitumor action of dimethyltriazenes

To investigate the role of monomethyltriazenes as the active metabolites of antitumor dimethyltriazenes, the in vivo simultaneous treatment with an inducer (phenobarbital, PB) or an inhibitor (carbon tetrachloride, CCl4) of hepatic drug metabolism was examined in mice bearing Lewis lung carcinoma. Treatment with PB or CCl4 with the dosage and schedules employed proved to be effective in markedly modifying the N-demethylation of the three dimethyltriazenes tested, as had been determined in vitro. No unambiguous increase by PB, or decrease by CCl4, which might theoretically be expected if metabolic conversion to monomethyltriazenes was involved, was observed for the antitumor and antimetastatic activity of dimethyltriazenes. At the same time, a difference was noted between the effects on primary tumors and those on metastases. These data support the view that generalizations on the relevance of monomethyltriazenes as the active metabolites responsible for the antitumor and antimetastatic activity of dimethyltriazenes may not be valid.