Angiogenesis alteration by defibrotide: implications for its mechanism of action in severe hepatic veno-occlusive disease.
Defibrotide (DF) is a mixture of porcine-derived single-stranded phosphodiester oligonucleotides (9-80-mer; average, 50-mer) that has been successfully used to treat severe hepatic veno-occlusive disease (sVOD) with multiorgan failure (MOF) in patients who have received cytotoxic chemotherapy in preparation for bone marrow transplantation. However, its mechanism of action is unknown. Herein, we show that DF and phosphodiester oligonucleotides can bind to heparin-binding proteins (eg, basic fibroblast growth factor [bFGF] but not vascular endothelial growth factor [VEGF] 165) with low nanomolar affinity. This binding occurred in a length- and concentration-dependent manner. DF can mobilize proangiogenic factors such as bFGF from their depot or storage sites on bovine corneal endothelial matrix. However, these molecules do not interfere with high-affinity binding of bFGF to FGFR1 IIIc but can replace heparin as a required cofactor for binding and hence cellular mitogenesis. DF also protects bFGF against digestion by trypsin and chymotrypsin and from air oxidation. In addition, DF binds to collagen I with low nanomolar affinity and can promote human microvascular endothelial cell-1 (HMEC-1) cell mitogenesis and tubular morphogenesis in three-dimensional collagen I gels. Thus, our data suggest that DF may provide a stimulus to the sinusoidal endothelium of a liver that has suffered a severe angiotoxic event, thus helping to ameliorate the clinical sVOD/MOF syndrome.
Benimetskaya
Luba
L
Albert Einstein-Montefiore Cancer Center, Montefiore Medical Center, Depertment of Oncology, Bronx, NY, USA.
Wu
Sijian
S
Voskresenskiy
Anatoliy M
AM
Echart
Cinara
C
Zhou
Jin-Feng
JF
Shin
Joongho
J
Iacobelli
Massimo
M
Richardson
Paul
P
Ayyanar
Kanyalakshmi
K
Stein
C A
CA
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002417:Cattle; D002461:Cell Line, Transformed; D003315:Cornea / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006504:Hepatic Veno-Occlusive Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009102:Multiple Organ Failure / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011089:Polydeoxyribonucleotides / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C036901:defibrotide; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3