Effect of alternative temozolomide schedules on glioblastoma O(6)-methylguanine-DNA methyltransferase activity and survival

Br J Cancer. 2010 Aug 10;103(4):498-504. doi: 10.1038/sj.bjc.6605792. Epub 2010 Jul 13.


Background: O(6)-methylguanine-DNA methyltransferase (MGMT) expression in glioblastoma correlates with temozolomide resistance. Dose-intense temozolomide schedules deplete MGMT activity in peripheral blood mononuclear cells; however, no published data exist evaluating the effect of temozolomide schedules on intracranial tumour MGMT activity.

Methods: Human glioblastoma cells (GBM43) with an unmethylated MGMT promoter were implanted intracranially in immunodeficient rodents. Three weeks later, animals received temozolomide 200 mg m(-2) for 5 days (schedule A, standard dose) or 100 mg m(-2) for 21 days (schedule B, dose intense).

Results: Tumour MGMT activity was depleted by day 6 in both treatment groups compared with baseline. O(6)-methylguanine-DNA methyltransferase activity returned to baseline by day 22 in the schedule A group, but remained suppressed in the schedule B group. By day 29, MGMT activity had returned to baseline in both groups. Mean tumour volume was significantly decreased compared with untreated controls with either schedule (P<0.01), although neither schedule was superior (P=0.60). Median survival was 64, 42, and 28 days for schedule A, schedule B, and no drug, respectively (P<0.001 A or B vs control, P=NS A vs B).

Conclusions: Dose-intense temozolomide prolongs tumour MGMT activity depletion compared with standard dosing, however, survival was not improved in this model.

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology
  • Antineoplastic Agents, Alkylating / therapeutic use*
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / mortality
  • Cell Line, Tumor
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / pharmacology
  • Dacarbazine / therapeutic use
  • Dose-Response Relationship, Drug
  • Glioblastoma / metabolism*
  • Glioblastoma / mortality
  • Humans
  • O(6)-Methylguanine-DNA Methyltransferase / biosynthesis*
  • Rats
  • Survival Analysis
  • Temozolomide
  • Tumor Burden / drug effects


  • Antineoplastic Agents, Alkylating
  • Dacarbazine
  • O(6)-Methylguanine-DNA Methyltransferase
  • Temozolomide