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    Targeting O6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy.

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    Authors
    Kaina, B
    Margison, Geoffrey P
    Christmann, M
    Affiliation
    Institute of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, 55131, Mainz, Germany. kaina@uni-mainz.de
    Issue Date
    2010-11
    
    Metadata
    Show full item record
    Abstract
    O (6)-methylguanine-DNA methyltransferase (MGMT) repairs the cancer chemotherapy-relevant DNA adducts, O (6)-methylguanine and O (6)-chloroethylguanine, induced by methylating and chloroethylating anticancer drugs, respectively. These adducts are cytotoxic, and given the overwhelming evidence that MGMT is a key factor in resistance, strategies for inactivating MGMT have been pursued. A number of drugs have been shown to inactivate MGMT in cells, human tumour models and cancer patients, and O (6)-benzylguanine and O (6)-[4-bromothenyl]guanine have been used in clinical trials. While these agents show no side effects per se, they also inactivate MGMT in normal tissues and hence exacerbate the toxic side effects of the alkylating drugs, requiring dose reduction. This might explain why, in any of the reported trials, the outcome has not been improved by their inclusion. It is, however, anticipated that, with the availability of tumour targeting strategies and hematopoetic stem cell protection, MGMT inactivators hold promise for enhancing the effectiveness of alkylating agent chemotherapy.
    Citation
    Targeting O6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy. 2010, 67 (21):3663-81 Cell Mol Life Sci
    Journal
    Cellular and Molecular Life Sciences
    URI
    http://hdl.handle.net/10541/115723
    DOI
    10.1007/s00018-010-0491-7
    PubMed ID
    20717836
    Type
    Article
    Language
    en
    ISSN
    1420-9071
    ae974a485f413a2113503eed53cd6c53
    10.1007/s00018-010-0491-7
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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