O6-Methylguanine-DNA methyltransferase in pediatric primary brain tumors: relation to patient and tumor characteristics.
The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) confers resistance to methylating and chloroethylating agents in pediatric medulloblastoma- and glioma-derived cell lines and xenografts. Here, we assayed MGMT activity in 110 pediatric brain tumors to establish correlates with patient and tumor characteristics. We also assayed MGMT in histologically normal brain adjacent to 22 tumors to characterize changes in activity accompanying neurocarcinogenesis. MGMT activity was detected in 94% of tumors, ranging ca. 1,500-fold from 0.34 to 498 fmol/10(6) cells (approximately 205-300,000 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 diagnostic 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 activity in tumors was 9-fold higher than in adjacent histologically normal brain (21 +/- 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 from 2- to >590-fold. Moreover, 67% of Mer- normal tissue was accompanied by Mer+ tumor. These observations indicate that MGMT activity is frequently elevated during pediatric neurocarcinogenesis. Significantly, enhanced MGMT activity may heighten resistance to alkylating agents, suggesting a potential role for MGMT inhibitors in therapy.
Bobola
M S
MS
Department of Surgery, Children's Hospital and Regional Medical Center, Seattle, Washington 98105, USA. mbobol@chmc.org
Berger
M S
MS
Ellenbogen
R G
RG
Roberts
T S
TS
Geyer
J R
JR
Silber
J R
JR
D000293:Adolescent; D000367:Age Factors; D001921:Brain / Q000201:enzymology*; D001932:Brain Neoplasms / Q000201:enzymology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000096:biosynthesis*; D010641:Phenotype
D019853:O(6)-Methylguanine-DNA Methyltransferase