Enhanced DNA repair as a mechanism of resistance to cis-diamminedichloroplatinum(II).
Murine leukemia L1210 cells, either sensitive or resistant to the toxic action of the cancer chemotherapeutic agent cis-diamminedichloroplatinum(II), have been studied for potential differences in the formation and repair of drug-induced DNA damage. The sensitivity for these experiments was obtained by using the radiolabeled analogue [3H]-cis-dichloro(ethylenediamine)platinum(II). The resistant cells demonstrated a 40% reduction in drug accumulation but a qualitatively similar profile of DNA-bound adducts. These adducts resembled those previously characterized in pure DNA and represented intrastrand cross-links at GG, AG, and GNG (N is any nucleotide) sequences in DNA. Repair of these cross-links occurred in a biphasic manner: rapid for the first 6 h and then much slower. The resistant cells removed up to 4 times as many adducts during the rapid phase of repair. The extent of this repair did not directly correlate with the degree of resistance in that cells with 100-fold resistance were only slightly more effective at repair than cells with 20-fold resistance. Therefore, although enhanced DNA repair is thought to contribute markedly to drug resistance, other mechanisms for tolerance of DNA damage may also occur in these cells.
Eastman
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A
Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha 68105.
Schulte
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N
D000818:Animals; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000187:drug effects*; D004351:Drug Resistance / Q000235:genetics; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice
D004273:DNA, Neoplasm; D002945:Cisplatin