Enhanced Antitumor Efficacy of an Oncolytic Herpes Simplex Virus Expressing an Endostatin–Angiostatin Fusion Gene in Human Glioblastoma Stem Cell Xenografts

Abstract

Viruses have demonstrated strong potential for the therapeutic targeting of glioblastoma stem cells (GSCs). In this study, the use of a herpes simplex virus carrying endostatin–angiostatin (VAE) as a novel therapeutic targeting strategy for glioblastoma-derived cancer stem cells was investigated. We isolated six stable GSC-enriched cultures from 36 human glioblastoma specimens and selected one of the stable GSCs lines for establishing GSC-carrying orthotopic nude mouse models. The following results were obtained: (a) VAE rapidly proliferated in GSCs and expressed endo–angio in vitro and in vivo 48 h and 10 d after infection, respectively; (b) compared with the control gliomas treated with rHSV or Endostar, the subcutaneous gliomas derived from the GSCs showed a significant reduction in microvessel density after VAE treatment; (c) compared with the control, a significant improvement was observed in the length of the survival of mice with intracranial and subcutaneous gliomas treated with VAE; (d) MRI analysis showed that the tumor volumes of the intracranial gliomas generated by GSCs remarkably decreased after 10 d of VAE treatment compared with the controls. In conclusion, VAE demonstrated oncolytic therapeutic efficacy in animal models of human GSCs and expressed an endostatin–angiostatin fusion gene, which enhanced antitumor efficacy most likely by restricting tumor microvasculature development.

Antitumor activity of combined endostatin and thymidine kinase gene therapy in C6 glioma models

“…ES is a potent angiogenesis inhibitor with low‐toxicity and a promising potential for clinical use . ES has been shown to suppress the growth of glioma in animal models possibly by suppressing the development of tumor microvasculature . In accordance with these findings, we detected that ES reduced proliferation, inhibited migration and induced apoptosis of ECV304 cells.…”

“…Because of TK catalyzation, GCV can be converted into a toxic metabolite which inhibits DNA replication, cell proliferation and induces cell apoptosis . Endostatin (ES) is an angiogenesis inhibitor which opposes antiglioma activities, with the most probable mechanism of restricting tumor microvasculature development . The effect of combined TK and ES gene therapy on glioma has not yet been investigated.…”

Plasminogen and its fragments in rat brain: a plausible role for astrocytes in angiostatin generation

“…In the previous papers, angiostatins are described as constantly formed by several types of retina-resident cells [10]. So far, studies of angiostatins in brain tissue have been limited, with few exceptions [11][12][13], to effects of angiostatin-encoding genetic engineering constructions, which are expressed in the models of rat and human glioma cells developed for testing anti-angiogenic strategy for malignant brain tumor therapy [14,15].…”

Pediatric cancer gone viral. Part I: strategies for utilizing oncolytic herpes simplex virus-1 in children

“… 82 , 83 Antiangiogenesis proteins platelet factor 4 (CXCL4), angiostatin, endostatin, and vasculostatin have augmented oHSV targeting of gliomas in animal models. 84–86 …”