Modulation of drug resistance mediated by loss of mismatch repair by the DNA polymerase inhibitor aphidicolin.
Loss of expression of mismatch repair (MMR) proteins leads to resistance of tumor cells to a variety of DNA-damaging agents, including bifunctional alkylating and monofunctional methylating agents such as cis-diaminedichloroplatinum II (CDDP) and N'-methyl-N-nitrosourea (MNU). It has been suggested that coupling to cell death does not occur in the absence of MMR, but instead, DNA lesions are bypassed during replication, giving a drug-tolerant phenotype. In the present study, we have used aphidicolin (Ap), an inhibitor of DNA polymerases, to study the role of replicative bypass in drug resistance mediated by loss of MMR. We have examined the survival of matched ovarian carcinoma cell lines with known MMR status after sequential treatment with CDDP or MNU and Ap. We show that Ap increases the sensitivity of MMR-deficient cell lines to CDDP and MNU to a greater extent than their MMR-proficient counterparts. Furthermore, loss of MMR correlates with loss of CDDP-induced G2 arrest, but this is partially restored after Ap treatment. These data support Ap sensitizing drug-resistant cancer cells that have lost MMR to CDDP and MNU and suggest that the potential use of Ap as a modulator of drug resistance should be targeted to MMR-defective tumors.
Moreland
N J
NJ
Cancer Research Campaign Department of Medical Oncology, Cancer Research Campaign Beatson Laboratories, Glasgow, United Kingdom.
Illand
M
M
Kim
Y T
YT
Paul
J
J
Brown
R
R
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016590:Aphidicolin / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008770:Methylnitrosourea / Q000494:pharmacology*; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D016590:Aphidicolin; D008770:Methylnitrosourea; D000070957:MutL Protein Homolog 1; D002945:Cisplatin