Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Research Paper J Vasc Res 2010;47:481–493 DOI: 10.1159/000313876 Microvascular Endothelial Cell Responses in vitro and in vivo: Modulation by Zoledronic Acid and Paclitaxel? Maria Michailidou   a Hannah K. Brown   a Diane V. Lefley   a Alyson Evans   a Simon S. Cross   c Robert E. Coleman   a Nicola J. Brown   b Ingunn Holen   a Academic Units of a  Clinical Oncology, b  Surgical Oncology and c  Pathology, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK mation and proliferation, and increased endothelial necro- sis; the combination induced HuDMEC apoptosis and further enhanced the inhibition of tube formation and migration. The combination caused minimal effects on the normal mi- crovasculature in vivo, suggesting that this potential thera- peutic strategy is not associated with deleterious microvas- cular side-effects. Copyright © 2010 S. Karger AG, Basel Introduction Over the past decade there has been an increasing re- search effort to develop inhibitors of tumour angiogene- sis as anti-cancer therapies. Tumours up to 1 mm in diameter obtain oxygen and nutrients by passive diffu- sion. Small tumour cell populations subsequently stimu- late the angiogenic switch, recruiting endothelial cells (EC) from surrounding tissues, as well as endothelial pro- genitor cells that home from the bone marrow to the site of active angiogenesis via the circulation. This leads to the formation of a new vascular network that infiltrates and nourishes the tumour mass, facilitating tumour expan- sion. Key Words Anti-angiogenic therapy  Anti-vascular therapy  Dorsal microcirculation chamber  Endothelial cells  Paclitaxel  Zoledronic acid Abstract Background/Aims: 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-en- dothelial 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 func- tional assays including proliferation, migration, tubule for- mation and apoptosis. The in vivo effect of the drugs on the normal microvasculature was determined using the dorsal microcirculation chamber model. Results/Conclusion: Zole- dronic acid reduced human dermal microvascular endothe- lial cell (HuDMEC) proliferation, caused accumulation of cells in S phase, and inhibited migration, tube formation and Ra- p1a prenylation. Paclitaxel significantly inhibited tube for- Received: May 19, 2009 Accepted after revision: December 8, 2009 Published online: April 30, 2010 Dr. Ingunn Holen Academic Unit of Clinical Oncology DU 19, School of Medicine and Biomedical Sciences, University of Sheffield Beech Hill Road, Sheffield S10 2RX (UK) Tel. +44 114 271 3854, Fax +44 114 271 1711, E-Mail i.holen  @  sheffield.ac.uk © 2010 S. Karger AG, Basel 1018–1172/10/0476–0481$26.00/0 Accessible online at: www.karger.com/jvr N.J.B. and I.H. are joint senior authors.