Enhancement of hepatocarcinogenesis by sequential administration of chemicals: summation versus promotion effects.

A comparative study was made of the sequential administration of the liver carcinogen, diethylnitrosamine (DEN), or the liver tumor promoter, phenobarbital, given after the liver carcinogen, N-2-fluorenylacetamide (FAA). The effects of the second carcinogen on preneoplastic cellular lesions induced by the first carcinogen were comparable to the effects of the promoter. In addition, both sequential exposures enhanced the ultimate carcinogenic effect, although the combination of FAA followed by DEN resulted in a greater number of malignant neoplasms. Thus, enhancement of carcinogenesis by a second chemical cannot be used by itself as evidence of a promoting action. Approaches to the more precise definition of promoters include exclusion of genotoxicity, identification of epigenetic mechanisms and lack of a summation effect with administration prior to genotoxic carcinogens.