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dc.contributor.authorBarvaux, Vincent A
dc.contributor.authorRanson, Malcolm R
dc.contributor.authorBrown, Robert
dc.contributor.authorMcElhinney, R Stanley
dc.contributor.authorMcMurry, T Brian H
dc.contributor.authorMargison, Geoffrey P
dc.date.accessioned2009-08-21T10:00:38Z
dc.date.available2009-08-21T10:00:38Z
dc.date.issued2004-02
dc.identifier.citationDual repair modulation reverses Temozolomide resistance in vitro. 2004, 3 (2):123-7 Mol. Cancer Ther.en
dc.identifier.issn1535-7163
dc.identifier.pmid14985452
dc.identifier.urihttp://hdl.handle.net/10541/78128
dc.description.abstractTemozolomide is an alkylating agent that mediates its cytotoxic effects via O(6)-methylguanine (O(6)-meG) adducts in DNA and their recognition and processing by the postreplication mismatch repair system (MMR). O(6)-meG adducts can be repaired by the DNA repair protein O(6)-alkylguanine-DNA-alkyltransferase (MGMT), which therefore constitutes a major resistance mechanism to the drug. Resistance to Temozolomide can also be mediated by loss of MMR, which is frequently mediated by methylation of the hMLH1 gene promoter. Methylation of hMLH1 can be reversed by treatment of cells with 5-aza-2'-deoxycytidine, while the MGMT pseudosubstrate O(6)-(4-bromothenyl)guanine (PaTrin-2) can deplete MGMT activity. Using a drug-resistant cell line which expresses MGMT and has methylated hMLH1, we show that while either of these treatments can individually sensitize cells to Temozolomide, the combined treatment leads to substantially greater sensitization. The increased sensitization is not observed in matched MMR proficient cells.
dc.language.isoenen
dc.subjectCell Line Tumouren
dc.subjectCancer Proteinsen
dc.subject.meshAdaptor Proteins, Signal Transducing
dc.subject.meshBase Pair Mismatch
dc.subject.meshCarrier Proteins
dc.subject.meshCell Line, Tumor
dc.subject.meshDNA Damage
dc.subject.meshDNA Repair
dc.subject.meshDacarbazine
dc.subject.meshDrug Resistance
dc.subject.meshGuanine
dc.subject.meshHumans
dc.subject.meshNeoplasm Proteins
dc.subject.meshNuclear Proteins
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase
dc.titleDual repair modulation reverses Temozolomide resistance in vitro.en
dc.typeArticleen
dc.contributor.departmentPaterson Institute for Cancer Research and Christie Hospital, Manchester, United Kingdom.en
dc.identifier.journalMolecular Cancer Therapeuticsen
html.description.abstractTemozolomide is an alkylating agent that mediates its cytotoxic effects via O(6)-methylguanine (O(6)-meG) adducts in DNA and their recognition and processing by the postreplication mismatch repair system (MMR). O(6)-meG adducts can be repaired by the DNA repair protein O(6)-alkylguanine-DNA-alkyltransferase (MGMT), which therefore constitutes a major resistance mechanism to the drug. Resistance to Temozolomide can also be mediated by loss of MMR, which is frequently mediated by methylation of the hMLH1 gene promoter. Methylation of hMLH1 can be reversed by treatment of cells with 5-aza-2'-deoxycytidine, while the MGMT pseudosubstrate O(6)-(4-bromothenyl)guanine (PaTrin-2) can deplete MGMT activity. Using a drug-resistant cell line which expresses MGMT and has methylated hMLH1, we show that while either of these treatments can individually sensitize cells to Temozolomide, the combined treatment leads to substantially greater sensitization. The increased sensitization is not observed in matched MMR proficient cells.


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