Authors: Abdel Nasser Hosein Yi Chieh Lim Bryan Day Brett Stringer Stephen Rose Richard Head Leah Cosgrove Peter Sminia Michael Fay Jennifer H Martin
Publish Date: 2015/02/04
Volume: 122, Issue: 2, Pages: 263-271
Abstract
Glioblastoma multiforme GBM has nearly uniformly fatal with a median survival of less than 2 years While there have not been any novel antiGBM therapeutics approved for many years there has been the gradual accumulation of clinical data suggesting that the widely used anticonvulsant agent valproic acid VPA may significantly prolong survival in GBM patients This preclinical study aimed to determine the potential clinical utility of VPA in the treatment of GBM Primary GBM cells were treated with VPA as a monotherapy and in combination with temozolomide and irradiation At clinically achievable concentrations VPA was shown to be effective as a monotherapy agent in the five primary lines tested VPA was then used as a sensitizing agent to in vitro radiation and showed significant augmentation of in vitro irradiation therapy In addition when VPA radiation and temozolomide were combined an additive rather than synergistic effect was noted Gene expression profiling demonstrated close clustering of triple treated cells with VPA monotreated cells while untreated cells clustered closer with TMZirradiation dual treated cells These microarray data suggest a dominant role of VPA at the gene expression level when combining these different treatment options Moreover in an in vivo tumor transplantation model we were able to demonstrate an increase in animal survival when cells were pretreated with irradiationVPA and when triple treated These findings provide a significant rationale for the investigation of VPA in the treatment of GBM patientsRBWH Department of Neurosurgery RBWH patients with GBM consenting for brain cancer research on resected tissue Rotary Rockhampton RBWH Division of Cancer Care and RBWH Foundation for funding the brain biobank at QIMR Experiments were approved by the human ethics committee of the Queensland Institute of Medical Research QIMR and Royal Brisbane and Women’s Hospital RBWH
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