AbstractThe field of oncology has faced major challenges as cancer therapies are often associated with undesired adverse effects such as cardiotoxicity. Crizotinib treatment has been linked with acute incidences of QT trace prolongation and dysrhythmias in patients during clinical trials. Tyrosine kinase inhibitors primarily display cardiotoxicity due to their activity on multiple receptors.
This present study evaluated concentration dependent cardiotoxicity in adult male Sprague Dawley rat hearts and cultured myoblasts.
Renin angiotensin system antagonists are well known for their cardioprotective effects on the myocardium.
The aim of this study was to assess the potential for renin angiotensin antagonists to limit cardiotoxicity induced by crizotinib treatment.
Crizotinib treatment induced significant concentration dependent impairment of left ventricular developed pressure in isolated langendorff perfused rat hearts. Crizotinib treatment also induced significant concentration dependent infarct to risk ratio development and decreased cultured myoblast viability. It also increased cleaved caspase 3 activity, superoxide generation and disrupted calcium signalling.
Ramipril co-administration with crizotinib significantly improved left ventricular pressure, reduced infarct to risk ratio in isolated rat hearts. Ramipril co-administration with crizotinib significantly increased myoblast viability, decreased mitochondrial superoxide generation and decreased calcium signalling.
Losartan co-administration with crizotinib similarly improved left ventricular developed pressure, and decreased infarct to risk ratio development. Losartan co-administration with crizotinib significantly increased myoblast viability, decreased cleaved caspase 3 activity, decreased mitochondrial superoxide generation and calcium signalling.
To conclude, the data from this thesis demonstrate concentration dependent toxicity of tyrosine kinase inhibitor crizotinib. The study also presents data that highlights the possible benefit of renin angiotensin system antagonists against crizotinib induced cardiotoxicity.
|Date of Award||2022|
|Supervisor||Helen Maddock (Supervisor), Christopher Mee (Supervisor) & Afthab Hussain (Supervisor)|