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.