Enhanced excision repair of DNA damage due to cis-diamminedichloroplatinum(II) in resistant cervix carcinoma HeLa cells.

Chuck C.-K. Chao

Research output: Contribution to journalJournal Article peer-review

Abstract

We have previously reported a cisplatin-resistant HeLa cell line which exhibits overproduction of nuclear proteins preferential for cisplatin-modified DNA (Chao et al., Cancer Res. 51:601-605, 1991; Biochem. J. 277: 875-878, 1991). In this study, excision repair of cisplatin-DNA adducts in a resistant and a revertant cell lines was investigated using in situ detection of cisplatin-DNA adducts by an immunoassay and the measurement of repair-associated DNA strand breaks by a sensitive alkaline elution method. The resistant cells exhibited a 2-fold decrease in the accumulation of cisplatin-DNA adducts; whereas, the revertant cells showed a similar level of cisplatin-DNA adducts as the parental cells in the parallel experiment. Immediately following cisplatin treatment, the resistant and the revertant cells accumulated respectively approximately 50% and 90% cisplatin-DNA adducts of the parental cells. However, the kinetic patterns of repair rate following peak accumulation of cisplatin-DNA adducts (which took approximately 4 h) was the same in the three cell lines. This finding was supported by the measurement of repair-associated DNA strand breaks using alkaline elution which showed 1.6- and 1.5-fold increase in the resistant and the revertant cells respectively. In addition, following transfection with plasmid DNA carrying cisplatin damage, the resistant and the revertant cells displayed a 2.4- and 1.4-fold enhancement in host cell reactivation, respectively. Furthermore, the acquired resistance in HeLa cells was partially reversed by nontoxic aphidicolin, a DNA polymerase-alpha and DNA repair inhibitor. The results strongly suggest the improved excision repair of cisplatin-DNA adducts as a mechanism of phenotypic resistance of cells to cisplatin.
Original languageAmerican English
Pages (from-to)347-355
JournalEuropean Journal of Pharmacology
Volume268
Issue number3
DOIs
StatePublished - 1994

Keywords

  • Antibodies, Monoclonal/immunology
  • Cell Survival/drug effects
  • Chloramphenicol O-Acetyltransferase/metabolism
  • Cisplatin/metabolism
  • Cisplatin/pharmacology
  • DNA Adducts/metabolism
  • DNA Damage/physiology
  • DNA Repair/physiology
  • Drug Resistance
  • Enzyme-Linked Immunosorbent Assay
  • HeLa Cells
  • Humans
  • Transfection

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