DNA mismatch repair and acquired cisplatin resistance in E. coli and human ovarian carcinoma cells.
The contribution of defective DNA mismatch repair (MMR) to acquired resistance to cis-diamminedichloroplatinum(II) (cisplatin) has been investigated in two model systems: E coli dam mutants and the A2780 ovarian carcinoma cell line. Inactivation of MMR-as indicated by the acquisition of an elevated spontaneous mutator phenotype-was observed frequently among survivors of cisplatin-treated dam mutants. These survivors exhibited a stable resistance to further cisplatin treatment. In contrast, none of twelve independent clones of A2780 that had survived cisplatin exposure and acquired stable drug resistance were repair defective. None exhibited the hallmark methylation tolerant phenotype associated with a MMR defect, mRNAs encoding five MMR proteins were easily detectable in all twelve variants, and the levels of four key MMR proteins were similar to those in the repair proficient parental cells. Further analysis indicated two different mechanisms of acquired resistance in A2780. The first was a protective effect that reduced the level of DNA platination. The second was observed as a reduced sensitivity to cell cycle arrest after cisplatin treatment and a consequent reduced apoptosis. The data suggest that although loss of MMR is a significant mechanism of acquired drug resistance in dam bacteria, alterations related to DNA protection or cell cycle progression after drug damage appear to be more probable than abrogation of MMR as resistance modulators in human cells.
Massey
Andrew
A
Clare Hall Laboratories, London Research Institute, Cancer Research UK, South Mimms, EN6 3LD Herts, UK.
Offman
Judith
J
Macpherson
Peter
P
Karran
Peter
P
D002277:Carcinoma / Q000378:metabolism; D002945:Cisplatin / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics* / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004926:Escherichia coli / Q000378:metabolism; D005260:Female; D006801:Humans; D018895:Microsatellite Repeats; D010051:Ovarian Neoplasms / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D002945:Cisplatin