Trichostatin A and oncolytic HSV combination therapy shows enhanced antitumoral and antiangiogenic effects.
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.
Liu
Ta-Chiang
TC
Molecular Neurosurgery Laboratory, Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. tachiangliu@yahoo.com
Castelo-Branco
Pedro
P
Rabkin
Samuel D
SD
Martuza
Robert L
RL
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D003131:Combined Modality Therapy; D019938:Cyclin D1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D006367:HeLa Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy / Q000379:methods*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D018139:Simplexvirus / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014779:Virus Replication
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D011500:Protein Synthesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D019938:Cyclin D1; C012589:trichostatin A