Neuro-Oncology: Efficacy of clinically relevant temozolomide dosing schemes in glioblastoma cancer stem cell lines

Thursday, May 3, 2012

Efficacy of clinically relevant temozolomide dosing schemes in glioblastoma cancer stem cell lines

Abstract

The effectiveness of temozolomide (TMZ) dosing schemes and the "rechallenge" of recurrent glioblastoma (GBM) with TMZ are controversial. We therefore compared the efficacy of different TMZ dosing schemes against GBM cancer stem cell (CSC) lines in vitro. In O⁶-methyl-guanidine-methyl-transferase (MGMT)-negative CSC lines, all schedules (1 day on/27 days off, 5 days on/23 days off, 7 days on/7 days off, 21 days on/7 days off, continuous low-dose TMZ) depleted clonogenic cells. In TMZ-resistant CSC lines, the 7 days on/7 days off scheme showed higher toxicity as compared with the other schemes. However, clinically feasible concentrations remained ineffective in highly resistant CSC lines. In addition, none of the schedules induced long-term depletion of clonogenic cells even at the highest concentrations (up to 250 μM). After sublethal TMZ treatment for 5 days, TMZ rechallenge of recovering CSC lines remained effective. Our data advocate CSC lines as in vitro model to address clinical questions. Using this model, our data suggest the effectiveness of TMZ in MGMT-negative CSC lines and support the concept of TMZ rechallenge. The 7 days on/7 days off scheme consistently showed the best activity of all schedules in TMZ-resistant CSC lines.

Content Type Journal Article
Category Laboratory Investigation
Pages 1-8
DOI 10.1007/s11060-012-0878-4
Authors
- Dagmar Beier, Department of Neurology and JARA Brain, Hospital Medical School, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
- Beate Schriefer, Department of Neurology, Medical School, University of Regensburg, Universitätsstrasse 84, 93053 Regensburg, Germany
- Konstantin Brawanski, Department of Neurology, Medical School, University of Regensburg, Universitätsstrasse 84, 93053 Regensburg, Germany
- Peter Hau, Department of Neurology, Medical School, University of Regensburg, Universitätsstrasse 84, 93053 Regensburg, Germany
- Joachim Weis, Department of Neuropathology, Medical School, RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
- Jörg B. Schulz, Department of Neurology and JARA Brain, Hospital Medical School, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
- Christoph P. Beier, Department of Neurology and JARA Brain, Hospital Medical School, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany