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Title: Effects of zoledronic acid (ZOL) and paclitaxelon (PAC) angiogenesis in breast cancer
Author: Michailidou, Maria
ISNI:       0000 0001 3397 2357
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2007
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Zoledronic acid (ZOL; Zometa) is a N-bisphosphonate used in the treatment of tumour related bone disease in solid and haematologic malignancies. ZOL also possesses anti-angiogenic properties by interfering with endothelial cell (EC) function, however little is known about the effect of ZOL on microvascular EC similar to tumour EC. Paclitaxel (PAC; Taxo) is a commonly used chemotherapeutic agent that interferes with microtubule assembly, and its antiangiogenic properties remain to be established. ZOL and PAC have also been shown to have a synergistic effect on apoptosis in breast cancer cells when administered sequentially. The effects of ZOL (0-50JJM for 24-72h) and PAC (0-10nM for 24-72h) alone and in combination were investigated on human dermal microvascular (HuDMEC) and/or macrovascular EC (HUVEC) in vitro. This included effects on EC cell death, adhesion onto extracellular matrix components. proliferation. cell cycle. migration. tube formation, cytoskeletal integrity and prenylation of the GTPase Rap1a. Further studies on the effect of ZOL (50-150JJg/kg) and/or PAC (10-30mg/kg) on normal and tumour vasculature in vivo were performed. using the dorsal microvascular circulation chamber (DMC) model. ZOL reduced EC proliferation, accumulation of cells in the S phase. and further inhibited migration tube formation and Rap1 a prenylation. EC apoptosis using flow cytometry or adhesion on components of the extracellular matrix was not affected. PAC interfered with EC tube formation and increased levels of necrosis and proliferation. Combined treatment with ZOL and PAC induced apoptosis and further inhibited tube formation and migration per cell batch. In vivo studies showed that ZOL alone or in combination with PAC did not affect normal arteriole or venule diameter compared to baselin.e diameter (P>O.05). PAC reduced arteriolar diameter (PO.05). Immunohistochemistry for CD34 suggested reduction of CD34 expression in treated vs untreated mice. These data showed that combinations of ZOL and PAC have increased antiangiogeni~ effects in Vitro, compared to the single agents. In' vivo studies showed that combination treatment with ZOL and PAC did not affect diameter of the normal vasculature.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available