Recombinant human VEGF165b protein is an effective anti-cancer agent in mice.
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.
Rennel
Emma S
ES
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
Hamdollah-Zadeh
Maryam A
MA
Wheatley
Edward R
ER
Magnussen
Anette
A
Schüler
Yvonne
Y
Kelly
Sara P
SP
Finucane
Ciara
C
Ellison
David
D
Cebe-Suarez
Stephanie
S
Ballmer-Hofer
Kurt
K
Mather
Stephen
S
Stewart
Lorna
L
Bates
David O
DO
Harper
Steven J
SJ
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
D020533:Angiogenesis Inhibitors; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A