title: Recombinant human VEGF165b protein is an effective anti-cancer agent in mice.
abstract: Tumour growth is dependent on angiogenesis, the key mediator of which is vascular endothelial growth factor-A (VEGF-A). VEGF-A exists as two families of alternatively spliced isoforms - pro-angiogenic VEGF(xxx) generated by proximal, and anti-angiogenic VEGF(xxx)b by distal splicing of exon 8. VEGF(165)b inhibits angiogenesis and is downregulated in tumours. Here, we show for the first time that administration of recombinant human VEGF(165)b inhibits colon carcinoma tumour growth and tumour vessel density in nude mice, with a terminal plasma half-life of 6.2h and directly inhibited angiogenic parameters (endothelial sprouting, orientation and structure formation) in vitro. Intravenous injection of (125)I-VEGF(165)b demonstrated significant tumour uptake lasting at least 24h. No adverse effects on liver function or haemodynamics were observed. These results indicate that injected VEGF(165)b was taken up into the tumour as an effective anti-angiogenic cancer therapy, and provide proof of principle for the development of this anti-angiogenic growth factor splice isoform as a novel cancer therapy.
authors.affiliation: Microvascular Research Laboratories, Department of Physiology and Pharmacology, School of Veterinary Science, University of Bristol, Southwell Street, Bristol BS2 8EJ, United Kingdom. Emma.Rennel@bris.ac.uk
authors.forename: Emma S
authors.initials: ES
authors.lastname: Rennel
authors.forename: Maryam A
authors.initials: MA
authors.lastname: Hamdollah-Zadeh
authors.forename: Edward R
authors.initials: ER
authors.lastname: Wheatley
authors.forename: Anette
authors.initials: A
authors.lastname: Magnussen
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schüler
authors.forename: Sara P
authors.initials: SP
authors.lastname: Kelly
authors.forename: Ciara
authors.initials: C
authors.lastname: Finucane
authors.forename: David
authors.initials: D
authors.lastname: Ellison
authors.forename: Stephanie
authors.initials: S
authors.lastname: Cebe-Suarez
authors.forename: Kurt
authors.initials: K
authors.lastname: Ballmer-Hofer
authors.forename: Stephen
authors.initials: S
authors.lastname: Mather
authors.forename: Lorna
authors.initials: L
authors.lastname: Stewart
authors.forename: David O
authors.initials: DO
authors.lastname: Bates
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Harper
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000818:Animals; D001794:Blood Pressure; D002455:Cell Division / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D007279:Injections, Subcutaneous; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D020533:Angiogenesis Inhibitors; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A