An XPG DNA repair defect causing mutagen hypersensitivity in mouse leukemia L1210 cells.
One of the most widely used antitumor drugs is cis-diamminedichloroplatinum(II) (cisplatin), and mechanisms of cisplatin resistance have been investigated in numerous model systems. Many studies have used mouse leukemia L1210/0 as a reference wild-type cell line, and cisplatin-resistant subclones have been derived from it. Increased DNA excision repair capacity is thought to play a key role in the acquired cisplatin resistance, and this has influenced development of drugs for clinical trials. We report here that the L1210/0 line is in fact severely deficient in nucleotide excision repair of damaged DNA in vivo and in vitro. L1210/0 cell extracts could be complemented by extracts from repair-defective human xeroderma pigmentosum (XP) or rodent excision repair cross-complementing (ERCC) mutant cells, except for XPG/ERCC5 mutants. Purified XPG protein could restore repair proficiency to L1210/0 extracts. Expression of mouse XPG mRNA was similar in all L1210 lines studied, suggesting a point mutation or small alteration of XPG in L1210/0 cells. The DNA repair capacity of a cisplatin-resistant subline, L1210/DDP10, is similar to that of type culture collection L1210 cells and to those of other normal mammalian cell lines. Nucleotide excision repair of DNA is thus clearly important in the intrinsic cellular defense against cisplatin. However, in contrast to what is generally believed, enhancement of DNA repair above the normal level in these rodent cells does not appear to be a mechanism of acquired resistance to the drug.
Vilpo
J A
JA
Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Hertfordshire, United Kingdom.
Vilpo
L M
LM
Szymkowski
D E
DE
O'Donovan
A
A
Wood
R D
RD
D000818:Animals; D001483:Base Sequence; D002945:Cisplatin / Q000633:toxicity*; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D017931:DNA Primers / Q000737:chemistry; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D004351:Drug Resistance; D004720:Endonucleases; D015870:Gene Expression; D007939:Leukemia L1210; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors; D014466:Ultraviolet Rays; D000099250:DNA Excision Repair Protein ERCC-5
D002945:Cisplatin; D004247:DNA; D017931:DNA Primers; D004268:DNA-Binding Proteins; D004720:Endonucleases; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5