Evidence of differential cisplatin-DNA adduct formation, removal and tolerance of DNA damage in three human lung carcinoma cell lines

Anticancer Drugs. 1993 Aug;4(4):491-500. doi: 10.1097/00001813-199308000-00011.

Abstract

The expression of intrinsic resistance to cisplatin in two lung cancer cell lines, one derived from a small cell carcinoma (SW1271) and the other from an adenocarcinoma (A549), relative to a drug-sensitive small cell line SW900, was characterized by: (i) expression of cross-resistance to mitomycin C and cadmium chloride, but increased sensitivity to adriamycin and etoposide; (ii) significantly decreased cisplatin uptake; (iii) elevated levels of glutathione which could be reduced by buthionine L-sulfoximine resulting in significant sensitization of the cells to cisplatin; (iv) a lack of consistent modification of metallothionein content and expression of levels of glutathione S-transferase, glutathione reductase and glutathione peroxidase or of activities of DT-diaphorase or catalase; (v) significantly reduced total DNA-platination levels immediately following a 1 h cisplatin treatment with 10 micrograms/ml (33.3 microM); (vi) increased removal of Pt-GG and Pt-AG adducts by the A549 cells, consistent with increased repair capacity, but a lack of removal of these major adducts by the SW1271 cells indicative of tolerance of this drug-induced DNA damage. These data therefore provide evidence of differential formation, repair and tolerance of DNA damage following exposure of three human lung carcinoma cell lines to cisplatin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / enzymology
  • Adenocarcinoma / metabolism
  • Carcinoma, Small Cell / drug therapy*
  • Carcinoma, Small Cell / enzymology
  • Carcinoma, Small Cell / metabolism*
  • Catalase / metabolism
  • Cisplatin / metabolism*
  • Cisplatin / pharmacokinetics
  • Cisplatin / toxicity*
  • DNA / metabolism*
  • DNA Adducts*
  • DNA Damage*
  • DNA Repair*
  • DNA, Neoplasm / drug effects
  • DNA, Neoplasm / metabolism*
  • Drug Resistance
  • Drug Screening Assays, Antitumor
  • Gene Expression
  • Glutathione / metabolism
  • Glutathione Peroxidase / metabolism
  • Glutathione Reductase / metabolism
  • Glutathione Transferase / metabolism
  • Humans
  • Kinetics
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / metabolism*
  • Metallothionein / genetics
  • Metallothionein / metabolism
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • Tumor Cells, Cultured

Substances

  • DNA Adducts
  • DNA, Neoplasm
  • cisplatin-DNA adduct
  • DNA
  • Metallothionein
  • Catalase
  • Glutathione Peroxidase
  • NAD(P)H Dehydrogenase (Quinone)
  • Glutathione Reductase
  • Glutathione Transferase
  • Glutathione
  • Cisplatin