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The specific role of O6-methylguanine-DNA methyltransferase inhibitors in cancer chemotherapy

    Guohui Sun

    Beijing Key Laboratory of Environment & Viral Oncology, College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124, PR China

    ,
    Lijiao Zhao

    *Author for correspondence: Tel.: +86 10 67391667; Fax: +86 10 67392001;

    E-mail Address: zhaolijiao@bjut.edu.cn

    Beijing Key Laboratory of Environment & Viral Oncology, College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124, PR China

    ,
    Rugang Zhong

    Beijing Key Laboratory of Environment & Viral Oncology, College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124, PR China

    &
    Yongzhen Peng

    National Engineering Laboratory for Advanced Municipal Wastewater Treatment & Reuse Technology, Engineering Research Center of Beijing, Beijing University of Technology, Beijing 100124, PR China

    Published Online:https://doi.org/10.4155/fmc-2018-0069

    The DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT), can confer resistance to guanine O6-alkylating agents. Therefore, inhibition of resistant MGMT protein is a practical approach to increase the anticancer effects of such alkylating agents. Numerous small molecule inhibitors were synthesized and exhibited potential MGMT inhibitory activities. Although they were nontoxic alone, they also inhibited MGMT in normal tissues, thereby enhancing the side effects of chemotherapy. Therefore, strategies for tumor-specific MGMT inhibition have been proposed, including local drug delivery and tumor-activated prodrugs. Over-expression of MGMT in hematopoietic stem cells to protect bone marrow from the toxic effects of chemotherapy is also a feasible selection. The future prospects and challenges of MGMT inhibitors in cancer chemotherapy were also discussed.

    Graphical abstract

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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