HUMAN BRAIN-TUMOR O-6-METHYLGUANINE-DNA METHYLTRANSFERASE MESSENGER-RNA AND ITS SIGNIFICANCE AS AN INDICATOR OF SELECTIVE CHLOROETHYLNITROSOUREA CHEMOTHERAPY

O-6-methylguanine-DNA methyltransferase (MGMT) removes and repairs chl oroethylnitrosourea (CENU)-induced O-6-methylguanine-DNA by accepting the alkyl group at a cysteine moiety. MGMT activity is, therefore, pre dictive of resistance or sensitivity to CENU chemotherapy. We measured the levels of MGMT mRNA expression in human brain tumors using a reve rse transcription-polymerase chain reaction (RT-PCR) method, and studi ed the significance of MGMT mRNA levels in CENU chemotherapy. The leve r of MGMT mRNA was represented as a percentage relative to the MGMT mR NA in U138MG brain tumor cells. Forty-three patients with brain tumors were entered into the study. High-grade gliomas had significantly low er levels of MGMT mRNA than did low-grade gliomas and non-glial tumors (p < 0.05 determined by analysis of covariance). Out of 14 high-grade gliomas, 4 had a level of MGMT mRNA below 10%, indicating chemosensit ivity to CENU. Out of 11 patients who received CENU chemotherapy, 3 ha d a partial response. All 3 responders had a tow level of MGMT mRNA. T he time to tumor progression (TTP) for 6 patients with a level lower t han the median was short, but significantly longer than the TTP for 5 patients with a higher level (P < 0.05 determined by Gehan's Wilcoxon test). These results indicate that a fraction of brain tumors have a l ow expression of MGMT mRNA, and that the level of MGMT mRNA is a usefu l indicator of effectiveness in selective CENU chemotherapy. (C) 1996 Wiley-Liss, Inc.