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

Background: O⁶-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 (P0.60). 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, PNS A vs B). Conclusions: Dose-intense temozolomide prolongs tumour MGMT activity depletion compared with standard dosing, however, survival was not improved in this model.