O-6-methylguanine-DNA methyltransferase in pediatric primary brain tumors:Relation to patient and tumor characteristics

The DNA repair protein O-6-methylguanine-DNA methyltransferase (MGMT) confe rs resistance to methylating and chloroethylating agents in pediatric medul loblastoma- and glioma-derived cell lines and xenografts, Here, we assayed MGMT activity in 110 pediatric brain tumors to establish correlates with pa tient and tumor characteristics. We also assayed MGMT in histologically nor mal brain adjacent to 22 tumors to characterize changes in activity accompa nying neurocarcinogenesis, MGMT activity was detected in 94% of tumors, ran ging ca, 1,500-fold from 0.34 to 498 fmol/10(6) cells (similar to 205-300,0 00 molecules/cell). Mean activity was 25 +/- 66 fmol/10(6) cells, including six specimens with undetectable activity (Mer(-) phenotype; <0.25 fmol/10( 6) cells or 151 molecules/cell). MGMT content varied 10-fold among diagnost ic groups and was associated with degree of malignancy, as evidenced by a 4 -fold difference in activity between high- and low-grade tumors (P = 0.03), Tumor MGMT content was age dependent, being 5-fold higher in children 3-12 years old than in infants (P = 0.015) and adolescents (P = 0.015), Mean ac tivity in tumors was 9-fold higher than in adjacent histologically normal b rain (21 <plus/minus> 44 versus 2.4 +/- 4.0 fmol/10(6) cells; P = 0.05), By comparing tumor and adjacent normal tissue from the same patient, we found that 68% of cases exhibited an elevation of tumor activity that ranged fro m 2- to > 590-fold. Moreover, 67% of Mer(-) normal tissue was accompanied b y Mer(+) tumor, These observations indicate that MGMT activity is frequentl y elevated during pediatric neurocarcinogenesis, Significantly, enhanced MG MT activity may heighten resistance to alkylating agents, suggesting a pote ntial role for MGMT inhibitors in therapy.