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

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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.
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.