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    Dual repair modulation reverses Temozolomide resistance in vitro.

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    Authors
    Barvaux, Vincent A
    Ranson, Malcolm R
    Brown, Robert
    McElhinney, R Stanley
    McMurry, T Brian H
    Margison, Geoffrey P
    Affiliation
    Paterson Institute for Cancer Research and Christie Hospital, Manchester, United Kingdom.
    Issue Date
    2004-02
    
    Metadata
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    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.
    Citation
    Dual repair modulation reverses Temozolomide resistance in vitro. 2004, 3 (2):123-7 Mol. Cancer Ther.
    Journal
    Molecular Cancer Therapeutics
    URI
    http://hdl.handle.net/10541/78128
    PubMed ID
    14985452
    Type
    Article
    Language
    en
    ISSN
    1535-7163
    Collections
    All Christie Publications
    All Paterson Institute for Cancer Research

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