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

Mar 13, 2013Neuro-oncology

Limited effectiveness of extended temozolomide treatment in brain tumor models without MGMT gene methylation

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Abstract

Protracted temozolomide therapy may improve survival in specific glioblastoma subtypes, with varying effectiveness across different genetic backgrounds.

Protracted temozolomide therapy showed superior survival in one of four MGMT promoter hypermethylated glioblastoma lines.
Standard temozolomide therapy outperformed placebo in two of three MGMT unmethylated glioblastoma lines.
Elevated MGMT levels were observed in mice treated with protracted temozolomide, suggesting a possible mechanism for treatment resistance.
A second model indicated that high MGMT levels in GBM14 flank xenografts were associated with acquired resistance to temozolomide.
Gene expression analysis revealed enrichment for cell cycle control and DNA damage checkpoint processes in TMZ-resistant GBM14 cells.

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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.

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

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