Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models.
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.
['Cen|Ling|L|', 'Carlson|Brett L|BL|', 'Pokorny|Jenny L|JL|', 'Mladek|Ann C|AC|', 'Grogan|Patrick T|PT|', 'Schroeder|Mark A|MA|', 'Decker|Paul A|PA|', 'Anderson|S Keith|SK|', 'Giannini|Caterina|C|', 'Wu|Wenting|W|', 'Ballman|Karla V|KV|', 'Kitange|Gaspar J|GJ|', 'Sarkaria|Jann N|JN|']
D000818:Animals D018906:Antineoplastic Agents, Alkylating D017209:Apoptosis D001932:Brain Neoplasms D049109:Cell Proliferation D019175:DNA Methylation D015254:DNA Modification Methylases D045643:DNA Repair Enzymes D003606:Dacarbazine D004305:Dose-Response Relationship, Drug D005909:Glioblastoma 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 D023041:Xenograft Model Antitumor Assays
temozolomide xenografts glioblastoma multiforme dosing schedule