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Title: Investigating tumour response to the anti-vascular drug combretastatin A₄ using magnetic resonance imaging and spectroscopy
Author: Dyke, Stephanie Odette Mary
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2005
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Anti-vascular cancer therapy is based on experimental evidence that the growth of solid tumours relies on the development and continual expansion of a host-derived vascular network to feed the proliferating mass of cancer cells. Combretastatin A4 (CA4) has emerged as a promising anti-vascular drug as it specifically damages tumour vasculature, leading to extensive secondary cancer cell death, without significantly impairing healthy tissue perfusion. The aim of this research was to further our understanding of CA4’s mode of action, and in particular address the hypothesis that CA4 is active upon proliferating (angiogenic) but not quiescent blood vessels in vivo. Two experimental approaches using human tumour models xenografted in mice were adopted for this purpose. In the first, tumour vascular proliferation was limited within a CA4-senstivie tumour model using the anti-angiogenic drug, vascular endothelial growth factor (VEGF) receptor tyrosine-kinase inhibitor\SU. This was shown to significantly reduce the tumour’s vascular response to CA4 treatment as assessed by magnetic resonance imaging and spectroscopy. Secondly, a relatively CA4-resistant tumour model was genetically modified to overexpress VEGF, a major mediator of the angiogenic process. The vasculature of these tumours was shown to be sensitised to the vascular-damaging effects of CA4. The results of this research suggest that CA4 specifically targets angiogenic tumour vessels in vivo. This work provides a biological explanation for the drug’s specificity for tumour versus healthy vessels, and more specifically, can explain the wide variation in tumour response to this anti-vascular drug.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available