- Microvasc Res. 2009 Aug 6.
Metronomic administration of ibandronate and its anti-angiogenic effects in vitro.
Morgan C, Jeremiah S, Wagstaff J.
Human Cancer Studies Group, Institute of Life Sciences, Swansea University, Singleton Park, SA2 8PP, UK.
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.