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.


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.


CONCLUSIONS
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.
Morgan
Claire
C
Human Cancer Studies Group, Institute of Life Sciences, Swansea University, Singleton Park, SA2 8PP, UK. c.morgan@swansea.ac.uk
Jeremiah
Steve
S
Wagstaff
John
J
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors; D006801:Humans; D000077557:Ibandronic Acid; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000503:physiopathology; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D000077557:Ibandronic Acid