Metronomic administration of ibandronate and its anti-angiogenic effects in vitro

Background: Angiogenesis plays an essential role in the growth and metastatic development of tumours. Recent in vitro studies have reported bisphosphonates as having anti-angiogenic properties. They have been shown to inhibit proliferation, induce Apoptosis and decrease capillary-like tube formation, but often the in vitro concentrations and dosing schedules used do not reflect drug pharmacokinetics or clinical dosing regimens.

Materials and methods: Human umbilical vein endothelial cells were exposed to physiologically relevant doses of the bisphosphonate ibandronate, mimicking the clinical administration of oral ibandronate (1 h daily dosing over 8 days at concentrations ranging from 1-10 microM). Cellular growth characteristics were then assessed.

Results: Low-dose ibandronate (1.25-2 microM) significantly reduced endothelial cell growth, while 2 microM ibandronate also significantly reduced capillary-like tube formation and increased Apoptosis of endothelial cells compared to untreated cells. There was no significant difference in activity with doses above 2 microM. However, inhibiting bFGF stimulated cell growth increased VEGF expression.

Conclusion: This work has demonstrated that repeated low-dose drug administration (metronomic therapy) of ibandronate has certain anti-angiogenic properties by inhibiting the stimulatory effects of bFGF. However targeting the inhibition of bFGF alone is unlikely to be a successful approach for completely inhibiting angiogenesis due to the interplay between bFGF and VEGF.