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Mechanisms of Disease: temozolomide and glioblastoma—look to the future

Nature Clinical Practice Oncology volume 5, pages 476–486 (2008)Cite this article

Abstract

Glioblastoma is both the most common and most aggressive primary brain tumor. Until recently, the standard of care involved maximal safe surgical resection followed by radiation therapy with or without nitrosourea-based chemotherapy. In 2005, the results of a large clinical trial examining the role of adjuvant chemotherapy in management of newly diagnosed glioblastoma were published. This study created a new standard of adjuvant treatment, using concurrent and sequential temozolomide in the initial therapy of glioblastoma. A companion tumor biology study identified the prognostic role of O6-methylguanine-DNA methyltransferase (MGMT) status in patients with newly diagnosed glioblastoma. Several preliminary studies have been initiated to address the issue of resistance and suppression of MGMT activity, and have used alternative temozolomide dosing schedules and O6-guanine mimetic agents as substrates for MGMT. In addition, recent studies have attempted to define mechanisms responsible for the apparent synergy between temozolomide and radiotherapy. Lastly, an increased understanding of the molecular biology of glioblastoma has provided new leads for the adjuvant treatment of this disease. This Review summarizes new developments in treatment of glioblastoma and speculates on possible future treatment strategies for managing this aggressive cancer.

Key Points

  • Temozolomide (TMZ) as a single agent used concurrently and sequentially with radiation therapy is the new standard of care for patients with newly diagnosed glioblastoma who meet the EORTC/NCI trial pre-specified inclusion criteria

  • TMZ-induced resistance is predominantly mediated by two DNA repair mechanisms: MGMT and DNA mismatch repair, which increase exposure to TMZ, and direct inhibition of MGMT, which might circumvent both intrinsic and acquired resistance to TMZ

  • Synergy between TMZ and radiation therapy seems to involve an increased number of radiation-induced double-strand DNA breaks

  • Synergies between TMZ and targeted molecular therapeutics, in particular antiangiogenic and anti-integrin therapies, are being studied and promising preliminary results have been reported

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  1. both at the Departments of Neurology and Neurosurgical Surgery, MM Mrugala is Assistant Professor and MC Chamberlain is Professor, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,

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Correspondence to Marc C Chamberlain.

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Marc C Chamberlain is a Consultant for Schering–Plough and he also received honoraria and grant and research support from Schering–Plough. Maciej M Mrugala is a Consultant for Schering–Plough.

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Mrugala, M., Chamberlain, M. Mechanisms of Disease: temozolomide and glioblastoma—look to the future. Nat Rev Clin Oncol 5, 476–486 (2008). https://doi.org/10.1038/ncponc1155

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