Dual repair modulation reverses Temozolomide resistance in vitro.

2.50
Hdl Handle:
http://hdl.handle.net/10541/78128
Title:
Dual repair modulation reverses Temozolomide resistance in vitro.
Authors:
Barvaux, Vincent A; Ranson, Malcolm R; Brown, Robert; McElhinney, R Stanley; McMurry, T Brian H; Margison, Geoffrey P
Abstract:
Temozolomide 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.
Affiliation:
Paterson Institute for Cancer Research and Christie Hospital, Manchester, United Kingdom.
Citation:
Dual repair modulation reverses Temozolomide resistance in vitro. 2004, 3 (2):123-7 Mol. Cancer Ther.
Journal:
Molecular Cancer Therapeutics
Issue Date:
Feb-2004
URI:
http://hdl.handle.net/10541/78128
PubMed ID:
14985452
Type:
Article
Language:
en
ISSN:
1535-7163
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
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.en
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
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