Tumor promotion phenomena in two-stage carcinogenesis were systematically explored in various rodent species in conjunction with transplacental carcinogenesis. The relationship between molecular structure and promoting activity of various barbiturates, phthalic acid esters and benzodiazepin tranquilizers is investigated by sequential administration to animals of a transisent, low level exposure to a genotoxic carcinogen followed by the test agent under study. Organ specificities and interstrain and interspecies correlations in tumor promotion are investigated for clues to the mechanism(s) of action of tumor promoters. Barbital has been found to promote carcinogenesis in the rat renal cortical epithelium, as well as in the liver while phenobarbital was found to promote carcinogenesis in the liver and thyroid follicular parenchyma. Phenobaarbital also promoted hepatocarcinogenesis in adult mice but inhibited the same when the offspring were exposed to this drug before they became sexually mature. Long acting barbiturates, phenobarbital and barbital, promoted carcinogenesis in different tissues in mice and rats exposed transplacentally to N-alkylnitrosoureas and revealed a greater extent of initiation at several """"""""minor"""""""" sites than expected from tumor incidence data from offspring not given the promoters. A sequence of multiple low doses of nitrosomethylurea was found to be a useful broad spectrum tumor initiation regimen. The plasticizer, di-2-ethylhexyl-phthalate was found to promote transformation of JB6 mouse epidermal cells and act as a second stage promoter of mouse skin. Benzodiazepine tranquilizers, diazepam and oxazepam are strong promoters of hepatocarcinogenesis in adult mice. Premalignant JB6 mouse epidermal cells are used to investigated the mechanisms of tumor promotion by various drugs and environmental pollutants.
