Pathogenesis of cardiotoxicity induced by anthracyclines.

The Heart Hospital, University College London Hospitals, London, UK.
Seminars in Oncology (Impact Factor: 3.94). 07/2006; 33(3 Suppl 8):S2-7. DOI: 10.1053/j.seminoncol.2006.04.020
Source: PubMed

ABSTRACT Anthracyclines are potent anti-neoplastic drugs used in the treatment of solid and hematologic cancers. However, their use is limited by cumulative dose-related cardiotoxic adverse effects, which are progressive and irreversible from the first dose. Clinical trial data have shown that anthracycline cardiotoxicity is associated with slowly progressive deterioration of cardiac function, which continues for years after treatment cessation. Cardiac damage has been shown at cumulative doses as low as 200 mg/m2, well below levels currently assumed to induce injury. The widespread use of anthracyclines in childhood leukemia has resulted in an improved long-term prognosis; however, these patients are subsequently at high risk of developing long-term cardiac damage, with studies suggesting as many as 65% of survivors of childhood leukemia will develop cardiac abnormalities. Middle aged and elderly patients who are prone to cardiac disease may be more vulnerable to the cardiotoxic effects of anthracyclines. Therapies or strategies to prevent anthracycline-induced cardiotoxicity are essential; ideally, these should be initiated at the beginning of anthracycline therapy to reduce the possibility of cardiac damage and to ensure the optimal use of chemotherapy.

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    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 microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial 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 <50%. Troponin I levels positively correlated with delayed and peak gadolinium contrast enhancement, histopathological grading and diastolic dysfunction. In summary, subcellular cardiomyocyte degeneration was the earliest marker, followed by progressive functional decline and histopathological manifestations. Myocardial contrast enhancement and elevations in cTnI occurred later. However, all indices pre-dated 'clinical' LV dysfunction and thus warrant further evaluation as predictive biomarkers.
    Toxicological Sciences 03/2014; · 4.48 Impact Factor
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