title: Reversal of drug resistance in human tumor xenografts by 2'-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter.
abstract: Loss of DNA mismatch repair because of hypermethylation of the hMLH1 gene promoter occurs at a high frequency in a number of human tumors. A role for loss of mismatch repair (MMR) in resistance to a number of clinically important anticancer drugs has been shown. We have investigated whether the demethylating agent 2'-deoxy-5-azacytidine (DAC) can be used in vivo to sensitize MMR-deficient, drug-resistant ovarian (A2780/cp70) and colon (SW48) tumor xenografts that are MLH1 negative because of gene promoter hypermethylation. Treatment of tumor-bearing mice with the demethylating agent DAC at a nontoxic dose induces MLH1 expression. Re-expression of MLH1 is associated with a decrease in hMLH1 gene promoter methylation. DAC treatment alone has no effect on the growth rate of the tumors. However, DAC treatment sensitizes the xenografts to cisplatin, carboplatin, temozolomide, and epirubicin. Sensitization is comparable with that obtained by reintroduction of the hMLH1 gene by chromosome 3 transfer. Consistent with loss of MMR having no effect on sensitivity in vitro to Taxol, DAC treatment has no effect on the Taxol sensitivity of the xenografts. DAC treatment does not sensitize xenografts of HCT116, which lacks MMR because of hMLH1 mutation. Because there is emerging data on the role of loss of MMR in clinical drug resistance, DAC could have a role in increasing the efficacy of chemotherapy for patients whose tumors lack MLH1 expression because of hMLH1 promoter methylation.
authors.affiliation: Cancer Research Campaign Department of Medical Oncology, University of Glasgow, Bearsden, United Kingdom. Jane.Plumb@beatson.gla.ac.uk
authors.forename: J A
authors.initials: JA
authors.lastname: Plumb
authors.forename: G
authors.initials: G
authors.lastname: Strathdee
authors.forename: J
authors.initials: J
authors.lastname: Sludden
authors.forename: S B
authors.initials: SB
authors.lastname: Kaye
authors.forename: R
authors.initials: R
authors.lastname: Brown
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020137:Base Pair Mismatch; D016190:Carboplatin / Q000494:pharmacology; D002352:Carrier Proteins; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D004260:DNA Repair; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D009687:Nuclear Proteins; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D002352:Carrier Proteins; C501486:MLH1 protein, human; C501485:Mlh1 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000077209:Decitabine; D003606:Dacarbazine; D016190:Carboplatin; D000070957:MutL Protein Homolog 1; D001374:Azacitidine; D002945:Cisplatin; D000077204:Temozolomide