title: O6-methylguanine-DNA methyltransferase activity is associated with response to alkylating agent therapy and withMGMTpromoter methylation in glioblastoma and anaplastic glioma.
abstract: BACKGROUND
  CpG methylation in the O6-methylguanine-DNA methyltransferase (MGMT) promoter is associated with better outcome following alkylating agent chemotherapy in glioblastoma (GBM) and anaplastic glioma (AG). To what extent improved response reflects low or absent MGMT activity in glioma tissue has not been unequivocally assessed. This information is central to developing anti-resistance therapies.
  
  
  METHODS
  We examined the relationship of MGMT activity in 91 GBMs and 84 AGs with progression-free survival (PFS) following alkylator therapy and with promoter methylation status determined by methylation-specific PCR (MSP).
  
  
  RESULTS
  Cox regression analysis revealed that GBMs with high activity had a significantly greater risk for progression in dichotomous (P≤ 0.001) and continuous (P≤ 0.003) models, an association observed for different alkylator regimens, including concurrent chemo-radiation with temozolomide. Analysis of MGMT promoter methylation status in 47 of the GBMs revealed that methylated tumors had significantly lower activity (P≤ 0.005) and longer PFS (P≤ 0.036) compared to unmethylated tumors, despite overlapping activities. PFS was also significantly greater in methylatedvs. unmethylated GBMs with comparable activity (P≤ 0.005), and among unmethylated tumors with less than median activity (P≤ 0.026), suggesting that mechanisms in addition to MGMT promote alkylator resistance. Similar associations of MGMT activity with PFS and promoter methylation status were observed for AGs.
  
  
  CONCLUSIONS
  Our results provide strong support for the hypotheses that MGMT activity promotes alkylator resistance and reflects promoter methylation status in malignant gliomas.
  
  
  CONCLUSIONS
  MGMT activity is an attractive target for anti-resistance therapy regardless of methylation status.
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Bobola
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alnoor
authors.affiliation: Taipei Medical University Hospital, Department of Neurosurgery, 252 Wu-Xin Street, Taipei, Taiwan 110.
authors.forename: John Y-S
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA.
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Kolstoe
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Silbergeld
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rostomily
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA.
authors.forename: A
authors.initials: A
authors.lastname: Blank
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA ; Department of Neurology, University of Washington, Seattle, WA.
authors.forename: Marc C
authors.initials: MC
authors.lastname: Chamberlain
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA.
authors.forename: John R
authors.initials: JR
authors.lastname: Silber
keywords: DNA repair; brain tumor; clinical outcome; drug resistance