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

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.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.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.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.