Undersulfated, low-molecular-weight glycol-split heparin as an antiangiogenic VEGF antagonist.
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 (approximately 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.
Pisano
Claudio
C
Sigma-Tau Research Department, 0040 Pomezia, Rome, Italy.
Aulicino
Concetta
C
Vesci
Loredana
L
Casu
Benito
B
Naggi
Annamaria
A
Torri
Giangiacomo
G
Ribatti
Domenico
D
Belleri
Mirella
M
Rusnati
Marco
M
Presta
Marco
M
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D042783:Endothelial Cells / Q000502:physiology; D006493:Heparin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D006493:Heparin