title: Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models.
abstract: BACKGROUND
  Temozolomide (TMZ) is important chemotherapy for glioblastoma multiforme (GBM), but the optimal dosing schedule is unclear.
  
  
  METHODS
  The efficacies of different clinically relevant dosing regimens were compared in a panel of 7 primary GBM xenografts in an intracranial therapy evaluation model.
  
  
  RESULTS
  Protracted TMZ therapy (TMZ daily M-F, 3 wk every 4) provided superior survival to a placebo-treated group in 1 of 4 O(6)-DNA methylguanine-methyltransferase (MGMT) promoter hypermethylated lines (GBM12) and none of the 3 MGMT unmethylated lines, while standard therapy (TMZ daily M-F, 1 wk every 4) provided superior survival to the placebo-treated group in 2 of 3 MGMT unmethylated lines (GBM14 and GBM43) and none of the methylated lines. In comparing GBM12, GBM14, and GBM43 intracranial specimens, both GBM14 and GBM43 mice treated with protracted TMZ had a significant elevation in MGMT levels compared with placebo. Similarly, high MGMT was found in a second model of acquired TMZ resistance in GBM14 flank xenografts, and resistance was reversed in vitro by treatment with the MGMT inhibitor O(6)-benzylguanine, demonstrating a mechanistic link between MGMT overexpression and TMZ resistance in this line. Additionally, in an analysis of gene expression data, comparison of parental and TMZ-resistant GBM14 demonstrated enrichment of functional ontologies for cell cycle control within the S, G2, and M phases of the cell cycle and DNA damage checkpoints.
  
  
  CONCLUSIONS
  Across the 7 tumor models studied, there was no consistent difference between protracted and standard TMZ regimens. The efficacy of protracted TMZ regimens may be limited in a subset of MGMT unmethylated tumors by induction of MGMT expression.
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Cen
authors.forename: Brett L
authors.initials: BL
authors.lastname: Carlson
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Pokorny
authors.forename: Ann C
authors.initials: AC
authors.lastname: Mladek
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Grogan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Schroeder
authors.forename: Paul A
authors.initials: PA
authors.lastname: Decker
authors.forename: S Keith
authors.initials: SK
authors.lastname: Anderson
authors.forename: Caterina
authors.initials: C
authors.lastname: Giannini
authors.forename: Wenting
authors.initials: W
authors.lastname: Wu
authors.forename: Karla V
authors.initials: KV
authors.lastname: Ballman
authors.forename: Gaspar J
authors.initials: GJ
authors.lastname: Kitange
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality*; D049109:Cell Proliferation; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C528331:MGMT protein, mouse; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: dosing schedule; glioblastoma multiforme; temozolomide; xenografts