This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bobola, M. S. Articles by Silber, J. R. Search for Related Content PubMed PubMed Citation Articles by Bobola, M. S. Articles by Silber, J. R.

O⁶-Methylguanine-DNA Methyltransferase in Pediatric Primary Brain Tumors

Relation to Patient and Tumor Characteristics¹

Division of Neurosurgery, Department of Surgery [M. S. Bo., R. G. E., T. S. R.], and Division of Hematology/Oncology, Department of Pediatrics [J. R. G.], Children’s Hospital and Regional Medical Center, Seattle, Washington 98105; Department of Neurological Surgery, University of Washington, Seattle, Washington 98195-6470 [M. S. Bo., R. G. E., T. S. R., J. R. S.]; and Department of Neurological Surgery, University of California, San Francisco, California 94143-0112 [M. S. Be.]

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/10⁶ cells (205–300,000 molecules/cell). Mean activity was 25 ± 66 fmol/10⁶ cells, including six specimens with undetectable activity (Mer^- phenotype; <0.25 fmol/10⁶ 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/10⁶ 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.

This article has been cited by other articles:

				H. Rubie, J. Chisholm, A. S. Defachelles, B. Morland, C. Munzer, D. Valteau-Couanet, V. Mosseri, C. Bergeron, C. Weston, C. Coze, et al. Phase II Study of Temozolomide in Relapsed or Refractory High-Risk Neuroblastoma: A Joint Societe Francaise des Cancers de l'Enfant and United Kingdom Children Cancer Study Group New Agents Group Study J. Clin. Oncol., November 20, 2006; 24(33): 5259 - 5264. [Abstract] [Full Text] [PDF]

				M. S. Bobola, J. R. Silber, R. G. Ellenbogen, J. R. Geyer, A. Blank, and R. D. Goff O6-Methylguanine-DNA Methyltransferase, O6-Benzylguanine, and Resistance to Clinical Alkylators in Pediatric Primary Brain Tumor Cell Lines Clin. Cancer Res., April 1, 2005; 11(7): 2747 - 2755. [Abstract] [Full Text] [PDF]

				B. R. Rood, H. Zhang, and P. H. Cogen Intercellular heterogeneity of expression of the MGMT DNA repair gene in pediatric medulloblastoma Neuro-oncol, July 1, 2004; 6(3): 200 - 207. [Abstract] [PDF]

				A. Broniscer and A. Gajjar Supratentorial High-Grade Astrocytoma and Diffuse Brainstem Glioma: Two Challenges for the Pediatric Oncologist Oncologist, April 1, 2004; 9(2): 197 - 206. [Abstract] [Full Text] [PDF]

				C. P. Wild and J. Kleinjans Children and Increased Susceptibility to Environmental Carcinogens: Evidence or Empathy? Cancer Epidemiol. Biomarkers Prev., December 1, 2003; 12(12): 1389 - 1394. [Full Text] [PDF]

				G. P. Margison, A. C. Povey, B. Kaina, and M. F. Santibanez Koref Variability and regulation of O6-alkylguanine-DNA alkyltransferase Carcinogenesis, April 1, 2003; 24(4): 625 - 635. [Abstract] [Full Text] [PDF]

				C. Balana, J. L. Ramirez, M. Taron, Y. Roussos, A. Ariza, R. Ballester, C. Sarries, P. Mendez, J. J. Sanchez, and R. Rosell O6-methyl-guanine-DNA methyltransferase Methylation in Serum and Tumor DNA Predicts Response to 1,3-Bis(2-Chloroethyl)-1-Nitrosourea but not to Temozolamide Plus Cisplatin in Glioblastoma Multiforme Clin. Cancer Res., April 1, 2003; 9(4): 1461 - 1468. [Abstract] [Full Text] [PDF]

				L. S. Lashford, P. Thiesse, A. Jouvet, T. Jaspan, D. Couanet, P. D. Griffiths, F. Doz, J. Ironside, K. Robson, R. Hobson, et al. Temozolomide in Malignant Gliomas of Childhood: A United Kingdom Children's Cancer Study Group and French Society for Pediatric Oncology Intergroup Study J. Clin. Oncol., December 15, 2002; 20(24): 4684 - 4691. [Abstract] [Full Text] [PDF]

				S. L. Gerson Clinical Relevance of MGMT in the Treatment of Cancer J. Clin. Oncol., May 1, 2002; 20(9): 2388 - 2399. [Abstract] [Full Text] [PDF]