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Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

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Abstract

O6-methylguanine-DNA methyltransferase (MGMT) repairs the cancer chemotherapy-relevant DNA adducts, O6-methylguanine and O6-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 O6-benzylguanine and O6-[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.

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Acknowledgments

The work of B.K. and M.C. is supported by DFG, Ka724 and Deutsche Krebsstiftung. G.P.M. thanks Cancer Research UK and CHEMORES for support.

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Kaina, B., Margison, G.P. & Christmann, M. Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy. Cell. Mol. Life Sci. 67, 3663–3681 (2010). https://doi.org/10.1007/s00018-010-0491-7

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