Abstract
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.
Footnotes
- Received November 26, 1997.
- Accepted April 9, 1998.
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Send reprint requests to: Dr. Paola Perego, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. E-mail:perego{at}istitutotumori.mi.it
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This work was supported in part by Associazione Italiana per la Ricerca sul Cancro, Consiglio Nazionale delle Ricerche (Finalized Project ACRO), Italian Ministero della Sanita’ and by a research contract from Sanofi Research. This work was conducted in part by the Clayton Foundation for Research—California Division. Dr. Howell is a Clayton Foundation investigator.
- The American Society for Pharmacology and Experimental Therapeutics
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