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Title: Targeting tumour-associated angiogenesis with zoledronate
Author: Metcalf, Stephen
ISNI:       0000 0004 2749 5584
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 2012
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The Chorioallantoic Membrane (CAM) assay can be used to assess a treatment’s anti-angiogenic potential; but also, it can function as a tumour model in its own right. Tumourigenic cells are implanted in the embryo early in development, with these cells present before the development of the immune system, they are determined to be 'self.' From here, the tumour cells divide, usurp a blood supply for nutrients and oxygen and begin to form a tumour mass. This mass can then be subjected to treatments and can determine a treatment’s anti-angiogenic or anti-tumour efficacy. The recruitment of a blood supply, the process of angiogenesis, without which tumour cells cannot replicate beyond a defined volume as they are confined by the laws of diffusion. Zoledronate (ZA) has previously been shown to possess some anti-angiogenic properties. ZA is used clinically to treat cancer associated bone disease and, as a fourth generation bisphosphonate, is very effective at preventing skeletal remodelling. The target of nitrogen containing bisphosphonates, such as ZA, is the mevalonate pathway; this pathway is responsible for the generation of lipids used to anchor proteins to the plasma membrane. With fewer proteins anchored in the plasma membrane, pro-survival signalling pathways are adversely affected. The CAM assay was established and refined; multiple cancer cell lines and some human tumour tissue were engrafted, so displaying intriguing histological architecture. Real time biomarkers of tumour growth were also investigated. Examination of the molecular changes required for adaption from in vitro to tumour models revealed several interesting avenues of research, which are currently being pursued. The use of the CAM model in the evaluation of oncolytic viruses was also investigated, with results suggesting a model worthy of further investigation. ZA was shown to be cytotoxic to endothelial cells and induced apoptosis with little effect on the cell cycle. Treatment of endothelial cells with Vascular Endothelium Growth Factor (VEGF) increased their resistance to ZA-induced cytotoxicity. The concentration of ZA required to inhibit the growth, or induce cytotoxicity, in a panel of renal cancer cell lines were much greater than that of endothelial cells. Apoptosis and Caspase assays, as well as cell cycle analysis, varied in result between renal cancer cell lines. VEGF had no effect on the proliferation rate of these cancer cell lines and an appropriate in vivo dose of a vascular disruptor was proposed. Neither ZA nor VEGF had any effect on the rate of tumour growth, either in the CAM or murine flank models. Only the vascular disruptor managed to impede tumour growth, but only for a time. Overall, the CAM assay is a useful technique and further investigations will elucidate some of the molecular mechanisms behind it. ZA has a modest anti-angiogenic capability, but, its inability to hamper tumour growth, compared to that of an established drug, indicates further experimentation and analysis is required.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available