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

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

Human Cancer Studies Group, Institute of Life Sciences, Swansea University, Singleton Park, SA2 8PP, UK.

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 muM). Cellular growth characteristics were then assessed. RESULTS: Low-dose ibandronate (1.25-2 muM) significantly reduced endothelial cell growth, while 2 muM 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 muM. 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.