ToxSci Advance Access published March 27, 2014
An integrated characterisation of serological, pathological and functional events in doxorubicin-induced cardiotoxicity First authors: Cove-Smith & Woodhouse Running title: Integrated assessment of doxorubicin cardiotoxicity Laura Cove-Smith*†, Neil Woodhouse‡, Adam Hargreaves§, Jason Kirk§, Susan Smith§, Sally A. Price§, Melanie Marsden§, Catherine Betts§, Simon Brocklehurst§, Alison Backen*, John Radford†lll, Kim Linton MRCP†lll, Ruth Roberts§, Matthias Schmitt¶, Caroline Dive*, Jonathan
*Clinical & Experimental Pharmacology, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK. †Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX. ‡
Personalised Healthcare & Biomarkers, §Drug Safety & Metabolism, Innovative Medicines,
AstraZeneca R&D, Alderley Park Macclesfield, Cheshire. ¶North West Regional Heart Centre, University Hospital of South Manchester, Wythenshawe, Manchester, UK, M23 9LT. ||
MedTech West, Chalmers University of Technology, 41296 Gothenburg, Sweden.
lll
University of Manchester, Institute of Cancer Sciences, Oxford Road, Manchester M13 9PT.
Underlined authors contributed equally to this work. 1
Correspondence should be to HRM at current address – Drug Safety Evaluation, Vertex
Pharmaceuticals (Europe) Ltd, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire, OX14 4RW, UK. E-mail –
[email protected], Phone – +44 (0)1235 438328.
1
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Tugwood*, Paul D. Hockings§|| & Howard R. Mellor§1
Abstract
Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study we have utilised a rat model of progressive doxorubicin-induced cardiomyopathy, applying multiple approaches, including cardiac MRI, to provide the most comprehensive characterisation to date of the timecourse of serological, pathological and functional events underlying this toxicity. Hannover Wistar Rats were dosed with 1.25mg/kg doxorubicin weekly for 8 weeks followed by a 4 week off-dosing ‘recovery’ period. Electron
changes after a single dose. Histopathological analysis revealed progressive cardiomyocyte degeneration, hypertrophy/cytomegaly and extensive vacuolation after 2 doses. Extensive replacement fibrosis (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI
(including left ventricular ejection
fraction (LVEF), cardiac output and E/A ratio) declined progressively, reaching statistical significance after 2 doses and culminating in ‘clinical’ LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after 8 doses, importantly preceding the LVEF decline to
