Microvascular endothelial cell responses in vitro and in vivo: modulation by zoledronic acid and paclitaxel?
OBJECTIVE
The cytotoxic agent paclitaxel and the anti-resorptive drug zoledronic acid are used in the early and advanced breast cancer setting, respectively. Both agents have been demonstrated to have anti-tumour and anti-endothelial actions. Combining paclitaxel with zoledronic acid induces a synergistic increase in apoptotic breast cancer cell death in vitro, suggesting an increased anti-tumour effect in vivo, but any specific effects on the normal microvasculature and potential side-effects of this combination remain to be established.


METHODS
The effects of zoledronic acid and paclitaxel were investigated, alone and in combination, on human microvascular endothelial cells in vitro, using functional assays including proliferation, migration, tubule formation and apoptosis. The in vivo effect of the drugs on the normal microvasculature was determined using the dorsal microcirculation chamber model.


CONCLUSIONS
Zoledronic acid reduced human dermal microvascular endothelial cell (HuDMEC) proliferation, caused accumulation of cells in S phase, and inhibited migration, tube formation and Rap1a prenylation. Paclitaxel significantly inhibited tube formation and proliferation, and increased endothelial necrosis; the combination induced HuDMEC apoptosis and further enhanced the inhibition of tube formation and migration. The combination caused minimal effects on the normal microvasculature in vivo, suggesting that this potential therapeutic strategy is not associated with deleterious microvascular side-effects.
Michailidou
Maria
M
Academic Units of Clinical Oncology, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK.
Brown
Hannah K
HK
Lefley
Diane V
DV
Evans
Alyson
A
Cross
Simon S
SS
Coleman
Robert E
RE
Brown
Nicola J
NJ
Holen
Ingunn
I
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology* / Q000633:toxicity; D017368:Protein Prenylation; D013997:Time Factors; D000077211:Zoledronic Acid; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; C430803:RAP1A protein, human; D000077211:Zoledronic Acid; D020827:rap1 GTP-Binding Proteins; D017239:Paclitaxel