Targeting O6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy.
Affiliation
Institute of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, 55131, Mainz, Germany. kaina@uni-mainz.deIssue Date
2010-11
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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 SciJournal
Cellular and Molecular Life SciencesDOI
10.1007/s00018-010-0491-7PubMed ID
20717836Type
ArticleLanguage
enISSN
1420-9071ae974a485f413a2113503eed53cd6c53
10.1007/s00018-010-0491-7
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