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    Alkylpurine-DNA-N-glycosylase confers resistance to temozolomide in xenograft models of glioblastoma multiforme and is associated with poor survival in patients.

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    Authors
    Agnihotri, S
    Gajadhar, A
    Ternamian, C
    Gorlia, T
    Diefes, K
    Mischel, P
    Kelly, Joanna
    McGown, Gail
    Thorncroft, Mary R
    Carlson, B
    Sarkaria, J
    Margison, Geoffrey P
    Aldape, K
    Hawkins, C
    Hegi, M
    Guha, A
    Show allShow less
    Affiliation
    Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada. sameer.agnihotri@utoronto.ca
    Issue Date
    2012-01-03
    
    Metadata
    Show full item record
    Abstract
    Glioblastoma multiforme (GBM) is the most common and lethal of all gliomas. The current standard of care includes surgery followed by concomitant radiation and chemotherapy with the DNA alkylating agent temozolomide (TMZ). O⁶-methylguanine-DNA methyltransferase (MGMT) repairs the most cytotoxic of lesions generated by TMZ, O⁶-methylguanine. Methylation of the MGMT promoter in GBM correlates with increased therapeutic sensitivity to alkylating agent therapy. However, several aspects of TMZ sensitivity are not explained by MGMT promoter methylation. Here, we investigated our hypothesis that the base excision repair enzyme alkylpurine-DNA-N-glycosylase (APNG), which repairs the cytotoxic lesions N³-methyladenine and N⁷-methylguanine, may contribute to TMZ resistance. Silencing of APNG in established and primary TMZ-resistant GBM cell lines endogenously expressing MGMT and APNG attenuated repair of TMZ-induced DNA damage and enhanced apoptosis. Reintroducing expression of APNG in TMZ-sensitive GBM lines conferred resistance to TMZ in vitro and in orthotopic xenograft mouse models. In addition, resistance was enhanced with coexpression of MGMT. Evaluation of APNG protein levels in several clinical datasets demonstrated that in patients, high nuclear APNG expression correlated with poorer overall survival compared with patients lacking APNG expression. Loss of APNG expression in a subset of patients was also associated with increased APNG promoter methylation. Collectively, our data demonstrate that APNG contributes to TMZ resistance in GBM and may be useful in the diagnosis and treatment of the disease.
    Citation
    Alkylpurine-DNA-N-glycosylase confers resistance to temozolomide in xenograft models of glioblastoma multiforme and is associated with poor survival in patients. 2012, 122 (1):253-66 J Clin Invest
    Journal
    The Journal of Clinical Investigation
    URI
    http://hdl.handle.net/10541/230172
    DOI
    10.1172/JCI59334
    PubMed ID
    22156195
    Type
    Article
    Language
    en
    ISSN
    1558-8238
    ae974a485f413a2113503eed53cd6c53
    10.1172/JCI59334
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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