Species-specific differences in the toxicity and mutagenicity of the anticancer drugs mithramycin, chromomycin A3, and olivomycin

Abstract

Three structurally related anticancer drugs, mithramycin, chromomycin A3, and olivomycin, exhibited large differences (greater than 100-fold) in their toxicity towards cultured cells from various species. These differences are species related, as all cell lines from any one species showed similar sensitivity to the three drugs. Of the three species examined, namely, human, mouse, and Chinese hamster, human cells were found to be most sensitive to these drugs. However, no significant difference in toxicity was observed between normal human diploid fibroblasts and heteroploid cell lines established from tumors. The above drugs were found to induce mutants at the hypoxanthine-guanine phosphoribosyl-transferase locus (i.e., resistance to 6-thioguanine) and produced DNA strand breaks, in a dose-dependent manner, in cells from all three species. However, the concentrations of these drugs which produced similar mutagenic or DNA strand break responses differed greatly for cells from the three species, and a good correlation was observed between the toxic and the mutagenic concentrations of these drugs for cells from the three species examined. These studies provide strong evidence that the toxic and mutagenic concentrations of different substances could differ greatly between cells from human and other species and indicate that the results of such studies cannot always be extrapolated from animal to human situations. It is suggested that a knowledge of the relative toxicity of any chemical towards cultured cells from human versus test animal should prove of value in extrapolating the results from animal systems to humans.