Glioblastoma multiforme (GBM) has nearly uniformly fatal with a median survival 
of less than 2 years. While there have not been any novel anti-GBM therapeutics 
approved for many years, there has been the gradual accumulation of clinical 
data suggesting that the widely used anti-convulsant agent, valproic acid (VPA) 
may significantly prolong survival in GBM patients. This pre-clinical 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 mono-treated cells while untreated 
cells clustered closer with TMZ-irradiation 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 pre-treated with irradiation-VPA and when triple treated. These findings 
provide a significant rationale for the investigation of VPA in the treatment of 
GBM patients.