1. A novel non-containing-nitrogen bisphosphonate inhibits both in vitro and in vivo angiogenesis
- Author
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Michel Kraemer, Dominique Ledoux, Y. Leroux, Mélanie Di Benedetto, Marc Lecouvey, Yamina Hamma-Kourbali, and Olivier Oudar
- Subjects
Umbilical Veins ,Time Factors ,Angiogenesis ,Nitrogen ,Biophysics ,Mice, Nude ,Angiogenesis Inhibitors ,In Vitro Techniques ,Vascular endothelial growth inhibitor ,Biochemistry ,Neovascularization ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Mice ,In vivo ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,Molecular Biology ,Benzyl Alcohols ,Cells, Cultured ,Matrigel ,Diphosphonates ,Dose-Response Relationship, Drug ,Neovascularization, Pathologic ,Chemistry ,Cell Biology ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,Drug Combinations ,Vascular endothelial growth factor C ,Models, Chemical ,Immunology ,Cancer research ,Female ,Proteoglycans ,Collagen ,Endothelium, Vascular ,Laminin ,medicine.symptom ,Protein Processing, Post-Translational ,Cell Division ,Neoplasm Transplantation - Abstract
Bisphosphonates (BP) are powerful inhibitors of bone resorption and are widely used in the treatment of patients with metastasis-induced osteolysis. In the present study, we show that a novel non-nitrogen-containing BP (BP7033) that exhibits antitumor activity is a potent inhibitor of both in vivo and in vitro angiogenesis. When administered to mice, BP7033 inhibited tumoral angiogenesis (65% at 0.06mg/injection) as well as tumor growth (65% at 0.006mg/injection) in a tumor model of A431 cells xenografted in nude mice, with no sign of toxicity. Additionally, in vivo angiogenesis induced by vascular endothelial growth factor-containing Matrigel implants was reduced by 90% in the presence of BP7033 (0.6mg/plug). In vitro, BP7033 inhibited proliferation of human umbilical vein endothelial cells (HUVEC) (IC(50) value 3x10(-4) M) and completely prevented the formation of capillary-like tubules by HUVEC in Matrigel. Moreover, treatment of A431 cells by BP7033 induced an inhibition of Ras processing and a decrease in the secretion of both vascular endothelial growth factor and matrix metalloproteinase-2, two well-known stimulators of the proliferation and migration of endothelial cells. These findings indicate that this new BP compound has marked antiangiogenic properties and thus represents a promising candidate for treatment of malignant diseases with an angiogenic component.
- Published
- 2003