Glycobiology Advance Access originally published online on October 20, 2004
Glycobiology 2005 15(2):1C-6C; doi:10.1093/glycob/cwi007
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Glycobiology vol. 15 no. 2 © Oxford University Press 2005; all rights reserved.
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Undersulfated, low-molecular-weight glycol-split heparin as an antiangiogenic VEGF antagonist
2 Sigma-Tau Research Department, 0040 Pomezia, Rome, Italy; 3 G. Ronzoni Institute for Chemical and Biochemical Research, 20133 Milan, Italy; 4 Department of Human Anatomy and Histology, University of Bari, 70124 Bari, Italy; 5 Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, 25123 Brescia, Italy
1 To whom correspondence should be addressed; e-mail: presta{at}med.unibs.it
Received on May 28, 2004; revised on September 14, 2004; accepted on October 14, 2004
Vascular endothelial growth factor (VEGF) represents a target for antiangiogenic therapies in a wide spectrum of diseases, including cancer. As a novel strategy to generate nonanticoagulant antiangiogenic substances exploiting binding to VEGF while preventing receptor engagement, we assessed the VEGF-antagonist activity of a low-molecular-weight (LMW) compound (ST2184, Mw = 5800) generated by depolymerization of an undersulfated glycol-split heparin derivative. The parental compound was obtained by introducing regular sulfation gaps along the prevalently N-sulfated heparin regions, followed by glycol-splitting of all nonsulfated uronic acid residues (
50% of total uronic acid residues). ST2184 was endowed with a negligible anticoagulant activity after S.C. injection in mice. ST2184 binds VEGF165 as evaluated by its capacity to retard 125I-VEGF165 electrophoretic migration in a gel mobility shift assay and to prevent VEGF165 interaction with heparin immobilized onto a BIAcore sensor chip. Unlike heparin, ST2184 was unable to present 125I-VEGF165 to its high-affinity receptors in endothelial cells and inhibited VEGF165-induced neovascularization in the chick embryo chorioallantoic membrane. Undersulfated, LMW glycol-split heparins may therefore provide the basis for the design of novel nonanticoagulant angiostatic compounds.
Key words: angiogenesis / endothelium / growth factor receptor / heparin / VEGF
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