Genetic and physiological modulation of anthracycline-induced mutagenesis in Salmonella typhimurium

The genotoxic properties of adriamycin and daunomycin, anthracycline antibiotics effective in the treatment of a wide variety of malignancies, were examined in the Salmonella/Ames reverse-mutation test. A novel time- and temperature-dependent phenomenon that potentiates the mutagenicity of these compounds, termed mutational enhancement, is described. The results of congeneric and chemical attenuation studies imply that anthracycline-induced free radicals contribute substantively to the mutagenic potentials of adriamycin and daunomycin. These studies show that adriamycin and daunomycin are not simple intercalative compounds. Rather, anthracycline-induced mutagenesis entails at least two separate but intimately related steps, namely, intercalation within discrete base sequences and the free-radical-mediated events that ensue. Implications of the nonrandom and site-specific action of the anthracyclines are discussed.