SENSITIVITY OF CHO MUTANT-CELL LINES WITH SPECIFIC DEFECTS IN NUCLEOTIDE EXCISION-REPAIR TO DIFFERENT ANTICANCER AGENTS

Nucleotide excision repair (NER) is one of the major DNA repair system s in mammalian cells, able to remove a broad spectrum of unrelated les ions. In this report the role of ERCC (excision repair cross-complemen ting) 1, ERCC2, ERCC3, ERCC4 and ERCC6 genes in removing the lesions c aused by alkylating agents with different structures and mechanisms of action has been studied using UV-sensitive DNA repair-deficient mutan t CHO cell lines. We confirmed that ERCC1 and ERCC4 play a role in the repair of cis-diamminedichloroplatinum (DDP)- and Melphalan (L-PAM)-i nduced DNA damage, while a marginal role of ERCC2 and ERCC3 in the cel lular response to DDP and L-PAM treatment has been observed. Treatment with methylating agents (DM and MNNG) showed a lack of a preferential cytotoxicity between the parental and the different NER-deficient cel l lines, emphasizing the importance of other repair systems such as 3- methyladenine glycosylase and O-6 alkyl-guanine-DNA-alkyl-transferase. ERCC1, ERCC2, ERCC3 and ERCC4, but not ERCC6 gene products seem to be involved in removing the lesions caused by Tallimustine and CC1065, m inor groove alkylating agents that alkylate N3 adenine in a sequence-s pecific manner. ERCC6-deficient cells were as sensitive as the parenta l cell line to all the cytotoxic drugs tested, except DDP. These data emphasize the importance of the CHO mutant cell lines with specific de fects in the DNA repair system for investigating the mechanism of acti on of different anti-cancer agents. (C) 1996 Wiley-Liss, Inc.