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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.

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). O?-methylguanine-DNA methyltransferase (MGMT) repairs the most cytotoxic of lesions generated by TMZ, O?-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 N?-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.

SUBMITTER: Agnihotri S

PROVIDER: S-EPMC3248301 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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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.

Agnihotri Sameer S Gajadhar Aaron S AS Ternamian Christian C Gorlia Thierry T Diefes Kristin L KL Mischel Paul S PS Kelly Joanna J McGown Gail G Thorncroft Mary M Carlson Brett L BL Sarkaria Jann N JN Margison Geoffrey P GP Aldape Kenneth K Hawkins Cynthia C Hegi Monika M Guha Abhijit A

The Journal of clinical investigation 20111212 1

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 sensit ...[more]

PMID: 22156195

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Project description:ObjectivesTumour recurrence of glioblastoma multiforme (GBM) after initial treatment with surgical resection, radiotherapy and chemotherapy is an inevitable phenomenon. This retrospective cohort study compared the efficacy of interstitial high dose rate brachytherapy (HDR-BRT), re-resection and sole dose dense temozolomide chemotherapy (ddTMZ) in the treatment of recurrent glioblastoma after initial surgery and radiochemotherapy.DesignRetropective cohort study.SettingPrimary level of care with two participating centres. The geographical location was central Germany.ParticipantsFrom January 2005 to December 2010, a total of 111 patients developed recurrent GBM after initial surgery and radiotherapy with concomitant temozolomide. The inclusion criteria were as follows: (1) histology-proven diagnosis of primary GBM (WHO grade 4), (2) primary treatment with resection and radiochemotherapy, and (3) tumour recurrence/progression.InterventionsThis study compared retrospectively the efficacy of interstitial HDR-BRT, re-resection and ddTMZ alone in the treatment of recurrent glioblastoma.Primary and secondary outcome measuresMedian survival, progression free survival and complication rate.ResultsMedian survival after salvage therapy of the recurrence was 37, 30 and 26 weeks, respectively. The HDR-BRT group did significantly better than both the reoperation (p<0.05) and the ddTMZ groups (p<0.05). Moderate to severe complications in the HDR-BRT, reoperation and sole chemotherapy groups occurred in 5/50 (10%), 4/36 (11%) and 9/25 (36%) cases, respectively.ConclusionsCT-guided interstitial HDR-BRT attained higher survival benefits in the management of recurrent glioblastoma after initial surgery and radiotherapy with concurrent temozolomide in comparison with the other treatment modalities. The low risk of complications of the HDR-BRT and the fact that it can be delivered percutaneously in local anaesthesia render it a promissing treatment option for selected patients which should be further evaluated.

Dataset Information

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

Publications

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

Similar Datasets

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