Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models

Ling Cen, Brett L. Carlson, Jenny L. Pokorny, Ann C. Mladek, Patrick T. Grogan, Mark A. Schroeder, Paul A. Decker, S. Keith Anderson, Caterina Giannini, Wenting Wu, Karla V. Ballman, Gaspar J. Kitange, Jann N Sarkaria

Research output: Contribution to journalArticle

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Abstract

BackgroundTemozolomide (TMZ) is important chemotherapy for glioblastoma multiforme (GBM), but the optimal dosing schedule is unclear.MethodsThe efficacies of different clinically relevant dosing regimens were compared in a panel of 7 primary GBM xenografts in an intracranial therapy evaluation model.ResultsProtracted TMZ therapy (TMZ daily M-F, 3 wk every 4) provided superior survival to a placebo-treated group in 1 of 4 O6-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 O6- 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.ConclusionsAcross 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.

Original languageEnglish (US)
Pages (from-to)735-746
Number of pages12
JournalNeuro-Oncology
Volume15
Issue number6
DOIs
StatePublished - Jun 2013

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temozolomide
Methyltransferases
Glioblastoma
Heterografts
Placebos
G2 Phase
Therapeutics
Cell Cycle Checkpoints

Keywords

  • dosing schedule
  • glioblastoma multiforme
  • temozolomide
  • xenografts

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Cite this

Cen, L., Carlson, B. L., Pokorny, J. L., Mladek, A. C., Grogan, P. T., Schroeder, M. A., ... Sarkaria, J. N. (2013). Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models. Neuro-Oncology, 15(6), 735-746. https://doi.org/10.1093/neuonc/not010

Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models. / Cen, Ling; Carlson, Brett L.; Pokorny, Jenny L.; Mladek, Ann C.; Grogan, Patrick T.; Schroeder, Mark A.; Decker, Paul A.; Anderson, S. Keith; Giannini, Caterina; Wu, Wenting; Ballman, Karla V.; Kitange, Gaspar J.; Sarkaria, Jann N.

In: Neuro-Oncology, Vol. 15, No. 6, 06.2013, p. 735-746.

Research output: Contribution to journalArticle

Cen, L, Carlson, BL, Pokorny, JL, Mladek, AC, Grogan, PT, Schroeder, MA, Decker, PA, Anderson, SK, Giannini, C, Wu, W, Ballman, KV, Kitange, GJ & Sarkaria, JN 2013, 'Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models', Neuro-Oncology, vol. 15, no. 6, pp. 735-746. https://doi.org/10.1093/neuonc/not010
Cen L, Carlson BL, Pokorny JL, Mladek AC, Grogan PT, Schroeder MA et al. Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models. Neuro-Oncology. 2013 Jun;15(6):735-746. https://doi.org/10.1093/neuonc/not010
Cen, Ling ; Carlson, Brett L. ; Pokorny, Jenny L. ; Mladek, Ann C. ; Grogan, Patrick T. ; Schroeder, Mark A. ; Decker, Paul A. ; Anderson, S. Keith ; Giannini, Caterina ; Wu, Wenting ; Ballman, Karla V. ; Kitange, Gaspar J. ; Sarkaria, Jann N. / Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models. In: Neuro-Oncology. 2013 ; Vol. 15, No. 6. pp. 735-746.
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abstract = "BackgroundTemozolomide (TMZ) is important chemotherapy for glioblastoma multiforme (GBM), but the optimal dosing schedule is unclear.MethodsThe efficacies of different clinically relevant dosing regimens were compared in a panel of 7 primary GBM xenografts in an intracranial therapy evaluation model.ResultsProtracted TMZ therapy (TMZ daily M-F, 3 wk every 4) provided superior survival to a placebo-treated group in 1 of 4 O6-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 O6- 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.ConclusionsAcross 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.",
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T1 - Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models

AU - Cen, Ling

AU - Carlson, Brett L.

AU - Pokorny, Jenny L.

AU - Mladek, Ann C.

AU - Grogan, Patrick T.

AU - Schroeder, Mark A.

AU - Decker, Paul A.

AU - Anderson, S. Keith

AU - Giannini, Caterina

AU - Wu, Wenting

AU - Ballman, Karla V.

AU - Kitange, Gaspar J.

AU - Sarkaria, Jann N

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N2 - BackgroundTemozolomide (TMZ) is important chemotherapy for glioblastoma multiforme (GBM), but the optimal dosing schedule is unclear.MethodsThe efficacies of different clinically relevant dosing regimens were compared in a panel of 7 primary GBM xenografts in an intracranial therapy evaluation model.ResultsProtracted TMZ therapy (TMZ daily M-F, 3 wk every 4) provided superior survival to a placebo-treated group in 1 of 4 O6-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 O6- 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.ConclusionsAcross 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.

AB - BackgroundTemozolomide (TMZ) is important chemotherapy for glioblastoma multiforme (GBM), but the optimal dosing schedule is unclear.MethodsThe efficacies of different clinically relevant dosing regimens were compared in a panel of 7 primary GBM xenografts in an intracranial therapy evaluation model.ResultsProtracted TMZ therapy (TMZ daily M-F, 3 wk every 4) provided superior survival to a placebo-treated group in 1 of 4 O6-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 O6- 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.ConclusionsAcross 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.

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