Antitumoral and Antiangiogenic Efficacy of Bisphosphonates In Vitro and in a Murine RENCA Model

• Published in: Anticancer research Vol. 28; no. 2A; pp. 933 - 941
• Main Authors: SOLTAU, Jens, ZIRRGIEBEL, Ute, ESSER, Norbert, SCHÄCHTELE, Christoph, TOTZKE, Frank, UNGER, Clemens, MERFORT, Irmgard, DREVS, Joachim
• Format: Journal Article
• Language: English
• Published: Attiki International Institute of Anticancer Research 01.03.2008
• Subjects: Angiogenesis Inhibitors - therapeutic use; Animals; Biological and medical sciences; Bone Density Conservation Agents - therapeutic use; Carcinoma, Renal Cell - drug therapy; Cell Line, Tumor; Cell Proliferation - drug effects; Clodronic Acid - therapeutic use; Diphosphonates - therapeutic use; Disease Models, Animal; Drug Screening Assays, Antitumor; Female; Imidazoles - therapeutic use; Kidney Neoplasms - drug therapy; Medical sciences; Mice; Mice, Inbred BALB C; Protein Kinases - metabolism; Tumors; Antineoplastic agent; Animal model; Treatment efficiency; VEGF; Rodentia; Bisphosphonates; Density; In vitro; Angiogenesis; Vertebrata; Mammalia; Cancerology; Vascular endothelium growth factor; Mouse; Blood vessel; Circulatory system; Neovascularization; Antiangiogenic agent; RENCA; vessel density
• ISSN: 0250-7005; 1791-7530

Background: Bisphosphonates have shown direct antitumoral activity in vitro, in vivo and even in clinical studies, but the exact mechanism for this has not yet been elucidated. In this study the antiangiogenic potency of zoledronic acid and clodronate were evaluated. Materials and Methods: The effects of zoledronic acid and clodronate on the proliferation of endothelial cells and different tumor cells, and on the activity of protein kinases were investigated. Furthermore in vitro experiments were performed to evaluate the underlying antiangiogenic mechanism of action. Both bisphosphonates were examined in vivo at different doses and in daily subcutaneous application in a murine renal cell carcinoma model (RENCA). The antiangiogenic activity was evaluated by immunohistochemical staining (CD31) and by determination of mouse vascular endothelial growth factor (VEGF) serum concentration. Results: Zoledronic acid and clodronate inhibited proliferation of endothelial cells at lower concentrations than the different tumor cell lines did. This effect was more pronounced for zoledronic acid. The activity of almost all tested kinases was inhibited by zoledronic acid, whereas clodronate showed no effect. In the RENCA model, a significant effect of zoledronic acid on the primary tumor in a bell-shaped dose response curve with the highest efficacy between 100 Bg/kg 2×d and 200 Bg/kg 1×d, was observed. The mean vessel density (MVD) was significantly reduced by both bisphosphonates at different concentrations. This is the first report on increased mouse VEGF serum concentrations in the RENCA model. Conclusion: The results indicate that these bisphosphonates, particularly zoledronic acid, possess antitumoral and antiangiogenic activity.