Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid.
Bisphosphonate drugs inhibit osteoclastic bone resorption and are widely used to treat skeletal complications in patients with tumor-induced osteolysis. We now show that zoledronic acid, a new generation bisphosphonate with a heterocyclic imidazole substituent, is also a potent inhibitor of angiogenesis. In vitro, zoledronic acid inhibits proliferation of human endothelial cells stimulated with fetal calf serum, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (IC(50) values 4.1, 4.2, and 6.9 microM, respectively), and modulates endothelial cell adhesion and migration. In cultured aortic rings and in the chicken egg chorioallantoic membrane assay, zoledronic acid reduces vessel sprouting. When administered systemically to mice, zoledronic acid potently inhibits the angiogenesis induced by subcutaneous implants impregnated with bFGF [ED(50), 3 microg/kg (7.5 nmol/kg) s.c.]. These findings indicate that zoledronic acid has marked antiangiogenic properties that could augment its efficacy in the treatment of malignant bone disease and extend its potential clinical use to other diseases with an angiogenic component.
Novartis Pharma Research, WKL-125.901, CH-4002 Basel, Switzerland.
Jeanette
J
Wood
Karine
K
Bonjean
Stephan
S
Ruetz
Akeila
A
Bellahcène
Laetitia
L
Devy
Jean Michel
JM
Foidart
Vincent
V
Castronovo
Jonathan R
JR
Green
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D002823:Chorion / Q000737:chemistry; D004164:Diphosphonates / Q000494:pharmacology*; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006133:Growth Substances / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D019044:Image Cytometry; D007093:Imidazoles / Q000494:pharmacology*; D008222:Lymphokines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D000077268:Pamidronate; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000077211:Zoledronic Acid
D020533:Angiogenesis Inhibitors; D004164:Diphosphonates; D016228:Endothelial Growth Factors; D006133:Growth Substances; D007093:Imidazoles; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D000077211:Zoledronic Acid; D000077268:Pamidronate