Evidence of differential cisplatin-DNA adduct formation, removal and tolerance of DNA damage in three human lung carcinoma cell lines.
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.
Laboratory of Cellular Chemotherapy, Imperial Cancer Research Fund, London, UK.
S A
SA
Shellard
A M
AM
Fichtinger-Schepman
J S
JS
Lazo
B T
BT
Hill
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D002945:Cisplatin / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018736:DNA Adducts; D004273:DNA, Neoplasm; C057270:cisplatin-DNA adduct; D004247:DNA; D008668:Metallothionein; D002374:Catalase; D005979:Glutathione Peroxidase; D016660:NAD(P)H Dehydrogenase (Quinone); D005980:Glutathione Reductase; D005982:Glutathione Transferase; D005978:Glutathione; D002945:Cisplatin