Journal
EUROPEAN JOURNAL OF CANCER
Volume 44, Issue 13, Pages 1883-1894Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2008.05.027
Keywords
VEGF; VEGF(165)b; anti-angiogenesis; cancer inhibition; pharmacokinetics; liver toxicity
Categories
Funding
- Cancer Research UK [A5047]
- British Heart Foundation [BB2000003, BS06/005]
- National Kidney Research Fund [R15/2/2003]
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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 6.2 h and directly inhibited angiogenic parameters (endothelial sprouting, orientation and structure formation) in vitro. Intravenous injection of I-125-VEGF(165)b demonstrated significant tumour uptake lasting at least 24 h. 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. (C) 2008 Elsevier Ltd. All rights reserved.
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