Abstract
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 (IC50 values 4.1, 4.2, and 6.9 μM, 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 [ED50, 3 μg/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.
Footnotes
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↵1 These authors contributed equally to this study.
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Supported by a research grant from Novartis to V.C.
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DOI: 10.1124/jpet.102.035295
- Abbreviations:
- ZOL
- zoledronic acid
- PAM
- pamidronate
- HUVEC
- human umbilical vein endothelial cell(s)
- FCS
- fetal calf serum
- BrdU
- 5-bromo-2′-deoxyuridine
- VEGF
- vascular endothelial growth factor
- bFGF
- basic fibroblast growth factor
- ELISA
- enzyme-linked immunosorbent assay
- PI
- propidium iodide
- TUNEL
- terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling
- CAM
- chorioallantoic membrane
- Received February 26, 2002.
- Accepted April 24, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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