Oncolytic herpes simplex viruses (HSVs) possess direct oncolytic and 
antiangiogenic activities and are promising anticancer agents, but their 
efficacy, when used as single agents, leaves room for improvement. We 
investigated whether combination therapy of HSV with histone deacetylase 
inhibitor trichostatin A (TSA), an agent that also targets cancer cells and 
tumor vasculature, would result in enhanced efficacy. In vitro, TSA and G47Delta 
showed strong synergy of action against proliferating endothelial cells, varying 
degrees of synergistic action against most cancer cell lines, but no effect in 
quiescent, normal endothelial and prostate epithelial cells. Synergy is 
dependent on viral replication; however, it is not dependent on the dosing 
sequence of TSA and G47Delta, viral genetic alterations, infectivity, or 
replication kinetics of G47Delta. Using an isogenic cell system, we found that a 
high level of cellular cyclin D1 is also critically important for the 
interaction. Normal cells with low cyclin D1 levels were not subjected to 
toxicity by either agent. In tumor cells and proliferating endothelial cells, 
the combination treatment enhanced the inhibition of cyclin D1 and vascular 
endothelial growth factor (VEGF). Concurrent systemic TSA and intratumoral 
G47Delta administration resulted in enhanced antiangiogenesis and enhanced 
antitumoral efficacy in animal models. Therefore, combination treatment with TSA 
and oncolytic HSV provides a novel approach to cancer therapy.