The role of genes that affect response to radiation in determining sensitivity to
platinum-containing compounds was studied using a panel of 23 strains of the yeast Schizosaccharomyces pombe. The radiation-hypersensitive mutants all had the same genetic background and most of them contained mutations that disabled either cell cycle checkpoints or DNA repair. The tested
platinum compounds included
cisplatin and two complexes containing diaminocyclohexane (
oxaliplatin and
tetraplatin), two ammine/
cyclohexylamine complexes with different orientation of the leaving groups (
JM216 and
JM335) and a multinuclear
platinum complex (
BBR 3464). The cytotoxic effect of the selected
platinum complexes was evaluated by using a microtiter growth inhibition assay with a 48 hr exposure to
drug. The mutants fell into three groups with respect to sensitivity to
cisplatin: four mutants (rad2, -7, -11, -15) exhibited minimal change in sensitivity; fifteen mutants (rad4-6, -8-10, -12-14, -16-17, -19-21, and -22) were 5.1-21.7-fold hypersensitive; only rad1 and -3 mutants, defective in checkpoints, and rad18, defective in repair, displayed a marked
hypersensitivity. None of the mutants demonstrated appreciable change in sensitivity to
JM216 presumably as a consequence of a lack of resistance of the wild-type strain, whereas a moderate increase in sensitivity to
JM335 was observed for most of the mutants, and
hypersensitivity to
BBR3464 was observed only in rad1 and -3. No relevant changes in sensitivity to
tetraplatin were observed. Most of the mutants, with the exception of rad2, -7, and -15, were hypersensitive to
oxaliplatin. These findings demonstrate that specific mutations have disparate effects on the profile of sensitivity to different members of the same class of
cytotoxic agents, which provides genetic evidence that different mechanisms are involved in differential cytotoxicity induced by Pt compounds. The results also demonstrate the utility of such a panel of mutants, constructed on the same genetic background, for detecting specific cellular response; presumably, this reflects the recognition or processing of specific
DNA adducts. In conclusion, because the rad1 and rad3 gene products are determinants of cellular response to a large number of
platinum-containing compounds, the present results support a critical role of genes involved in cell cycle control in cellular sensitivity to these agents.