Formation and repair of DNA interstrand cross-links in relation to cytotoxicity and unscheduled DNA synthesis induced in control and mutant human cells treated with cis-diamminedichloroplatinum(II).
A comparative study was performed with a variety of human cell lines on the effects of treatments with cis-diamminedichloroplatinum(II) (cisplatin) on cell survival and the induction of unscheduled DNA synthesis. In addition to control fibroblasts (Han, MB), cell lines defective in DNA repair were used [xeroderma pigmentosum, XP(A) and XP(F), and Fanconi's anemia (FA)], as well as cells deficient in arylsulfatase A (mucolipidosis II, ML1 and ML2). Ultraviolet light and mitomycin C were included in this study as model DNA-damaging agents. Furthermore, induction of DNA interstrand cross-links by cisplatin and their repair were studied. As for survival, only XP cells were abnormally sensitive to ultraviolet light, and only FA cells were abnormally sensitive to mitomycin C. To cisplatin, however, all mutants tested were more sensitive (2 to 5 times) than were normal cells. Unscheduled DNA synthesis induction by ultraviolet light was strong in all but the XP cells; the other two agents did not induce unscheduled DNA synthesis. Induction of DNA interstrand cross-links by cisplatin was linear with dose. Formation continued for up to 18 to 24 h after treatment. During this period, all cells but the ML mutants responded similarly. In ML cells, much fewer cross-links were induced, which were repaired rapidly. In FA cells, accumulation continued for at least 96 h; in the other cells, most of the cross-links had been removed after that period. In the discussion, the cisplatin-induced DNA interstrand cross-links are proposed as an important potentially lethal lesion, in view of their persistence in the highly sensitive FA cells. Furthermore, the possible involvement of certain steps of the long-patch excision repair pathway in the removal of this lesion is considered. The sensitivity of ML cells to cisplatin is attributed to cytoplasmic effects, rather than to chromosomal damage.
D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects*; D005199:Fanconi Anemia / Q000378:metabolism; D006801:Humans; D016685:Mitomycin; D008937:Mitomycins / Q000494:pharmacology; D009154:Mutation; D014983:Xeroderma Pigmentosum / Q000378:metabolism
D008937:Mitomycins; D016685:Mitomycin; D004247:DNA; D002945:Cisplatin