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dc.contributor.authorAgnihotri, S
dc.contributor.authorGajadhar, A
dc.contributor.authorTernamian, C
dc.contributor.authorGorlia, T
dc.contributor.authorDiefes, K
dc.contributor.authorMischel, P
dc.contributor.authorKelly, Joanna
dc.contributor.authorMcGown, Gail
dc.contributor.authorThorncroft, Mary R
dc.contributor.authorCarlson, B
dc.contributor.authorSarkaria, J
dc.contributor.authorMargison, Geoffrey P
dc.contributor.authorAldape, K
dc.contributor.authorHawkins, C
dc.contributor.authorHegi, M
dc.contributor.authorGuha, A
dc.date.accessioned2012-06-22T10:03:03Z
dc.date.available2012-06-22T10:03:03Z
dc.date.issued2012-01-03
dc.identifier.citationAlkylpurine-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 Investen_GB
dc.identifier.issn1558-8238
dc.identifier.pmid22156195
dc.identifier.doi10.1172/JCI59334
dc.identifier.urihttp://hdl.handle.net/10541/230172
dc.description.abstractGlioblastoma 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.
dc.language.isoenen
dc.rightsArchived with thanks to The Journal of clinical investigationen_GB
dc.subject.meshAnimals
dc.subject.meshAntineoplastic Agents, Alkylating
dc.subject.meshCell Line, Tumor
dc.subject.meshDNA Glycosylases
dc.subject.meshDNA Modification Methylases
dc.subject.meshDNA Repair
dc.subject.meshDNA Repair Enzymes
dc.subject.meshDacarbazine
dc.subject.meshDrug Resistance, Neoplasm
dc.subject.meshGene Expression
dc.subject.meshGene Knockdown Techniques
dc.subject.meshGlioblastoma
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshMice, Inbred NOD
dc.subject.meshMice, SCID
dc.subject.meshRNA, Small Interfering
dc.subject.meshTumor Suppressor Proteins
dc.subject.meshXenograft Model Antitumor Assays
dc.titleAlkylpurine-DNA-N-glycosylase confers resistance to temozolomide in xenograft models of glioblastoma multiforme and is associated with poor survival in patients.en
dc.typeArticleen
dc.contributor.departmentArthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada. sameer.agnihotri@utoronto.caen_GB
dc.identifier.journalThe Journal of Clinical Investigationen_GB
html.description.abstractGlioblastoma 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.


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