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Mechanisms of Chemoresistance to Alkylating Agents in Malignant Glioma

Authors' Affiliations: ¹ Departments of Radiation Oncology and Pathology, Mayo Clinic, Rochester, Minnesota; ² Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, California; ³ Northern Institute for Cancer Research, University of Newcastle upon Tyne, Newcastle, England, United Kingdom; ⁴ Department of Neurology, University of Zürich, Zurich, Switzerland; and ⁵ Department of Neurooncology, University Clinic of Heidelberg, Heidelberg, Germany

Requests for reprints: Jann N. Sarkaria, Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Phone: 507-266-3877; Fax: 507-284-0079; E-mail: Sarkaria.Jann{at}mayo.edu.

Intrinsic or acquired chemoresistance to alkylating agents is a major cause of treatment failure in patients with malignant brain tumors. Alkylating agents, the mainstay of treatment for brain tumors, damage the DNA and induce apoptosis, but the cytotoxic activity of these agents is dependent on DNA repair pathways. For example, O⁶-methylguanine DNA adducts can cause double-strand breaks, but this is dependent on a functional mismatch repair pathway. Thus, tumor cell lines deficient in mismatch repair are resistant to alkylating agents. Perhaps the most important mechanism of resistance to alkylating agents is the DNA repair enzyme O⁶-methylguanine methyltransferase, which can eliminate the cytotoxic O⁶-methylguanine DNA adduct before it causes harm. Another mechanism of resistance to alkylating agents is the base excision repair (BER) pathway. Consequently, efforts are ongoing to develop effective inhibitors of BER. Poly(ADP-ribose)polymerase plays a pivotal role in BER and is an important therapeutic target. Developing effective strategies to overcome chemoresistance requires the identification of reliable preclinical models that recapitulate human disease and which can be used to facilitate drug development. This article describes the diverse mechanisms of chemoresistance operating in malignant glioma and efforts to develop reliable preclinical models and novel pharmacologic approaches to overcome resistance to alkylating agents.