Mechanisms of chemoresistance to alkylating agents in malignant glioma

Jann N. Sarkaria, Gaspar J. Kitange, C. David James, Ruth Plummer, Hilary Calvert, Michael Weller, Wolfgang Wick

Research output: Contribution to journalReview article

230 Scopus citations

Abstract

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, 06-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 06-methylguanine methyltransferase, which can eliminate the cytotoxic 06-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.

Original languageEnglish (US)
Pages (from-to)2900-2908
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number10
DOIs
StatePublished - May 15 2008

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sarkaria, J. N., Kitange, G. J., James, C. D., Plummer, R., Calvert, H., Weller, M., & Wick, W. (2008). Mechanisms of chemoresistance to alkylating agents in malignant glioma. Clinical Cancer Research, 14(10), 2900-2908. https://doi.org/10.1158/1078-0432.CCR-07-1719