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 and benzodiazepine tranquilizers were investigated by sequential administration to animals of a transient, low level exposure to a genotoxic carcinogen followed by the test agent under study. Two long-acting hypnotic barbiturates, allobarbital and aprobarbital, were found to promote liver carcinogenesis in male rats, while two monosubstituted nonhypnotic barbiturates lacked such activity. Adult inbred strains of mice were found to differ significantly in their susceptibility to the tumor promoting effects of phenobarbital; this susceptibility to tumor promotion appeared to be dominant since the F1 hybrids derived from a cross between the susceptible strain (DBA/2N) and the resistant strain (C57BL/6N) were suceptible to phenobarbital promotion. Unlike the rat and mouse, in Syrian hamsters liver parenchymal cells were resistent to tumor promotion by phenobarbital. Two widely used benzodiazepine tranquilizers, diazepam and oxazepam, were found to promote liver carcinogenesis in mice. Diazepam was more effective than oxazepam and its effect was proportionate to dose. Like a well-known rodent liver tumor promoter, phenobarbital, both diazepam and oxazepam induced hepatomegaly, cytochrome P-450 and cytochrome p-450-dependent aminopyrine N-demethylase activity in mouse hepatocytes.
