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10.1245/ASO.2005.03.081
Annals of Surgical Oncology 12:1025-1036 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Herpes Simplex Virus Amplicon Delivery of a Hypoxia-Inducible Soluble Vascular Endothelial Growth Factor Receptor (sFlk-1) Inhibits Angiogenesis and Tumor Growth in Pancreatic Adenocarcinoma

Maura Reinblatt, MD1, Richard H. Pin, MD1, William J. Bowers, PhD2, Howard J. Federoff, MD, PhD2 and Yuman Fong, MD1

1 Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021
2 Center for Aging and Developmental Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Correspondence: Address correspondence and reprint requests to: Yuman Fong, MD; E-mail: fongy{at}mskcc.org.

Background: Tumor hypoxia induces vascular endothelial growth factor (VEGF) expression, which stimulates angiogenesis and tumor proliferation. The VEGF signaling pathway is inhibited by soluble VEGF receptors (soluble fetal liver kinase 1; sFlk-1), which bind VEGF and block its interaction with endothelial cells. Herpes simplex virus (HSV) amplicons are replication-incompetent viruses used for gene delivery. We attempted to attenuate angiogenesis and inhibit pancreatic tumor growth through HSV amplicon–mediated expression of sFlk-1 under hypoxic control.

Methods: A multimerized hypoxia-responsive enhancer (10 x HRE) was cloned upstream of the sFlk-1 gene (10 x HRE/sFlk-1). A novel HSV amplicon expressing 10 x HRE/sFlk-1 was genetically engineered (HSV10 x HRE/sFlk-1). Human pancreatic adenocarcinoma cells (AsPC1) were transduced with HSV10 x HRE/sFlk-1 and incubated in normoxia (21% oxygen) or hypoxia (1% oxygen). Capillary inhibition was evaluated by human umbilical vein endothelial cell assay. Western blot assessed sFlk-1 expression. AsPC1 flank tumor xenografts (n = 24) were transduced with HSV10 x HRE/sFlk-1.

Results: Media from normoxic AsPC1 transduced with HSV10 x HRE/sFlk-1 yielded a 36% reduction in capillary formation versus controls (P < .05), whereas hypoxic AsPC1 yielded a 76% reduction (P < .005). Western blot of AsPC1 transduced with HSV10 x HRE/sFlk-1 demonstrated greater sFlk-1 expression in hypoxia versus normoxia. AsPC1 flank tumors treated with HSV10 x HRE/sFlk-1 exhibited a 59% reduction in volume versus controls (P < .000001).

Conclusions: HSV amplicon delivery of a hypoxia-inducible soluble VEGF receptor significantly reduces new vessel formation and tumor growth. Tumor hypoxia can thus be used to direct antiangiogenic therapy to pancreatic adenocarcinoma.

Key Words: Amplicon • Hypoxia • Flk-1 • Herpes simplex virus • Pancreatic cancer • Vascular endothelial growth factor






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