Induction of petite mutants in yeast by non-intercalative DNA-binding antitumour agents

A series of 17 bis-charged non-intercalative DNA-binding antitumour agents and 7 related inactive compounds have been tested for the induction of respiratory deficient (petite) mutants in Saccharomyces cerevisiae D5. Many compounds were strong inducers of petite mutants at concentrations which were not toxic to the growth of the yeast cells. Mutagenicity is only weakly correlated with in vitro inhibition of L1210 cell growth; however, mutagenicity, yeast toxicity and in vitro and in vivo antitumour activity are all correlated with selective binding to polydeoxy(adenylic-thymidylic) acid rather than polydeoxy(guanylic-cytidylic) acid, as measured by an ethidium competition assay. It is concluded that A-T-rich DNA may be a target for all the biological effects measured in this study. Furthermore, the possibility that the target for antitumour action may be tumour cell mitochondrial DNA is supported by these results.