Tumor promotion phenomena in two-stage carcinogenesis were systematically explored in various rodent species in conjunction with transplacental carcinogenesis. Structure-promoting activity relationships of various barbiturates, hydantoins, oxazolidinediones, and benzodiazepine tranquilizers were investi- gated by sequential administration to animals of a transient, low level exposure to a genotoxic carcinogen followed by the test agent under study. A close relationship was found to exist between the induction of certain cytochrome P-450 species and tumor-promoting abilities of barbiturates and hydantoins. Two oxazolidinediones, trimethadione and dimethadione, non-inducers of cytochrome P-450, failed to promote liver carcinogenesis in rats. Unlike diazepam and oxazepam, a benzodiazepine tranquilizer, clonazepam did not possess liver tumor-promoting activity in mice. Phenobarbital increased liver weight and enhanced hepatic alkoxyresorufin O- dealkylase and aminopyrine N-demethylase activities in rats, mice and patas monkeys susceptible to liver tumors but failed to induce any of these parameters to a significant extent in species resistant to liver tumor promotion, hamsters and cynomolgus monkeys.
