Herpes simplex virus amplicon delivery of a hypoxia-inducible angiogenic inhibitor blocks capillary formation in hepatocellular carcinoma Journal Article

  

Authors:	Pin, R. H.; Reinblatt, M.; Bowers, W. J.; Federoff, H. J.; Fong, Y.; Vickers, S.; Callery, M.
Article Title:	Herpes simplex virus amplicon delivery of a hypoxia-inducible angiogenic inhibitor blocks capillary formation in hepatocellular carcinoma
Abstract:	Tumor hypoxia induces vascular endothelial growth factor (VEGF) expression, which stimulates tumor angiogenesis. The VEGF pathway is inhibited by soluble VEGF receptors (soluble fetal liver kinase-1 [sFlk-1]) that bind VEGF and block its interaction with endothelial cells. Herpes simplex virus (HSV)-derived amplicons are replication-incompetent viruses used for gene delivery. We attempt to attenuate angiogenesis and inhibit hepatoma growth through amplicon-mediated expression of sFlk-1 under hypoxic control. A multimerized hypoxia-responsive enhancer (10xHRE) was cloned upstream of the sFlk-1 gene (10xHRE/sFlk-1). An amplicon expressing 10xHRE/sFlk-1 was genetically engineered (HSV10xHRE/sFlk-1). SK-HEP-1 human hepatoma cells were transduced with HSV10xHRE/sFlk-1 and incubated in normoxia (21% O2) or hypoxia (1% O2). Human umbilical vein endothelial cell assay evaluated capillary inhibition. Western blot assessed sFlk-1 expression. SK-HEP-1 flank tumors (n = 24) in athymic mice were treated with HSV10xHRE/sFlk-1. Media from hypoxic SK-HEP-1 transduced with HSV10xHRE/sFlk-1 yielded an 80% reduction in capillary formation (P < 0.005), whereas normoxic SK-HEP-1 yielded a 25% reduction (P < 0.05). Western blot of SK-HEP-1 transduced with HSV10xHRE/sFlk-1 demonstrated greater sFlk-1 expression in hypoxia vs. normoxia. SK-HEP-1 tumors treated with HSV10xHRE/sFlk-1 yielded a 72% reduction in volume vs. the control group (P < 0.000001). HSV amplicon-mediated delivery of a hypoxia-inducible soluble VEGF receptor substantially reduces new vessel formation and tumor growth in hepatoma. © 2004 The Society for Surgery of the Alimentary Tract.
Keywords:	dna binding protein; genetics; dna-binding proteins; angiogenesis inhibitor; liver cell carcinoma; carcinoma, hepatocellular; liver neoplasms; receptors, vascular endothelial growth factor; mouse; animal; metabolism; animals; mice; cells, cultured; vasculotropin receptor; nuclear protein; transcription factor; vascularization; gene vector; genetic vectors; transcription factors; nuclear proteins; blotting, western; cell culture; nude mouse; mice, nude; liver tumor; western blotting; vascular endothelial growth factor; gene therapy; simplexvirus; cell hypoxia; angiogenesis inhibitors; hypoxia inducible factor 1alpha; herpes simplex virus; hif1a protein, human; hypoxia-inducible factor 1, alpha subunit; hypoxia inducible factor 1; hypoxia-inducible factor 1; helix loop helix protein; helix-loop-helix motifs; flk-1; humans; human; article
Journal Title:	Journal of Gastrointestinal Surgery
Volume:	8
Issue:	7
ISSN:	1091-255X
Publisher:	Springer
Date Published:	2004-11-01
Start Page:	812
End Page:	823
Language:	English
DOI:	10.1016/j.gassur.2004.08.007
PROVIDER:	scopus
PUBMED:	15531234
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-16644370354&partnerID=40&md5=33102f1975340c14cf0d7b135401218b
Notes:	J. Gastrointest. Surg. -- Cited By (since 1996):14 -- Export Date: 16 June 2014 -- Source: Scopus

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