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

J Neurooncol. 2012 Aug;109(1):45-52. doi: 10.1007/s11060-012-0878-4. Epub 2012 Apr 29.


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 O(6)-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Alkylating / pharmacology*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • DNA Modification Methylases / metabolism
  • DNA Repair Enzymes / metabolism
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / pharmacology
  • Drug Resistance, Neoplasm
  • Flow Cytometry
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Temozolomide
  • Tumor Stem Cell Assay
  • Tumor Suppressor Proteins / metabolism


  • Antineoplastic Agents, Alkylating
  • Tumor Suppressor Proteins
  • Dacarbazine
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes
  • Temozolomide