MOHAMED, ASMA,K,I (2021) Preclinical Evaluation of Cardiotoxicity Associated with Vascular Disrupting Agents Used for the Treatment of Cancer. Doctoral thesis, Durham University.
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Author-imposed embargo until 30 June 2024.
The therapeutic value of vascular disrupting agents (VDAs) as cancer therapeutics is compromised by cardiovascular toxicity, a major limiting factor for clinical progression. In addition to causing vascular damage and subsequent indirect cardiotoxicity, there is now evidence to support an effect of VDAs upon cardiomyocyte pathophysiology and consequent direct cardiotoxicity. The aim of this project was to investigate effects of VDAs upon cardiac cells in vitro and thereby ascertain a molecular basis of VDA-induced cardiotoxicity, to drive
strategies for clinical mitigation of this toxicity. Using the human adult ventricular cell line (AC10) and the beating murine stem-cell derived cardiomyocytes (Cor.AT®), the VDAs Colchicine and Combretastatin-A4 both caused the
expected growth inhibition in proliferative cells, due to their effect on microtubular dynamics. However, VDAs were also shown to affect survival and function of quiescent cardiomyocytes, representative of the non-proliferative nature of the adult heart. Furthermore, VDAs at non toxic concentrations, also perturbed the contractile functionality of cardiac cells, as determined by impedance-based real-time cell analysis of stem-cell derived cardiomyocytes Cor.AT®. In terms of a mechanism, the preliminary investigations show that treatment with VDAs caused a concentration-dependent change in gene expression of several genes involved in apoptosis and
cell death, a pro-inflammatory response, vascular tonicity, extracellular-signal-regulated kinase (ERK) pathways, platelet activation and aggregation and ultimately vascular damage and cardiac remodelling. Taken together, these findings imply alternative toxicity mechanisms to mitotic arrest and cell cycle inhibition, involving induction of both a structural toxicity and
interruption of the contractile response of cardiomyocytes. The observation show that pre-treatment with agents targeting disruption of angiotensin-signaling may reduce VDA-mediated toxicity, analogous to that observed with anthracycline-induced cardiotoxicity, also suggests pharmacological strategies for clinical mitigation of VDA-induced toxicity may be possible.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Keywords:||Cardiovascular toxicity, cardiotoxicity, Colchicine, combretastatin A 4 Phosphate, tubulin, vascular disrupting agents, preclinical cardiac models.|
|Faculty and Department:||Faculty of Social Sciences and Health > Applied Social Sciences, School of|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||30 Jun 2021 12:35|