Pathogenesis of cardiotoxicity induced by anthracyclines
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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- "In light of this, we have undertaken a rigorous, integrated characterization of the serological, pathological, and functional events associated with the development of chronic DOXinduced cardiotoxicity in rat. In order to achieve this, we first aimed to identify a DOX dosing regimen in rat that resulted in a chronic, rather than acute, cardiomyopathy, consistent with clinical presentation (Elliott, 2006). Previously, in some studies , large single bolus doses of DOX, or multiple doses over 1–2 weeks, have been administered to rodents to evoke acute cardiotoxicity (Arola et al., 2000; Czarnecki, 1984; Takasaye et al., 2004). "
ABSTRACT: The incidence of drug-induced structural cardiotoxicity which may lead to heart failure, has been recognised in association with the use of anthracycline anti-cancer drugs for many years, but has also been shown to occur following treatment with the new generation of targeted anti-cancer agents that inhibit one or more receptor or non-receptor tyrosine kinases, serine/threonine kinases as well as several classes of non-oncology agents. A workshop organised by the MRC Centre for Drug Safety Science (University of Liverpool) on 5 September 2013 and attended by industry, academia and regulatory representatives, was designed to gain a better understanding of the gaps in the field of structural cardiotoxicity that can be addressed through collaborative efforts. Specific recommendations from the workshop for future collaborative activities included: greater efforts to identify predictive (a) preclinical and (b) clinical biomarkers of early cardiovascular injury, c) improved understanding of comparative physiology/pathophysiology and the clinical predictivity of current pre-clinical in vivo models, d) the identification and use of a set of cardiotoxic reference compounds for comparative profiling in improved animal and human cellular models, e) more sharing of data (through publication/consortia arrangements) on target related toxicities, f) strategies to develop cardio-protective agents and g) closer interactions between pre-clinical scientists and clinicians to help ensure best translational efforts.British Journal of Pharmacology 10/2014; 172(4). DOI:10.1111/bph.12979 · 4.99 Impact Factor
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- "Although the exact mechanisms of anthracyclines damage to heart myocytes is unknown, there are several hypotheses (11). Elevations in serum cardiac troponins (T and I), representing a potential marker of damage, are associated with damage to heart cells (12). "
ABSTRACT: Background Anthracyclines are important components of many chemotherapeutic protocols. The present study aimed to evaluate the repolarization changes in electrocardiography (ECG) which may predict drug induced arrhythmia. Materials and Methods In this cross-sectional study, the recorded ECGs were assessed for QT dispersion (QTd), QT corrected dispersion (QTcd), T peak to Tend dispersion (TPed), and P dispersion (Pd) in 12 ECG leads. The demographic information, including sex, age, and duration of drug consumption, were recorded, as well. Results In this study, 112 patients, including 58 females (52%) and 54 males (48%) with the mean age of 8.7±4.5 years, as the case group were compared with 43 children, including 17 males (40%) and 26 females (60%), in the control group. Most of our patients (88%) had received usual doses of anthracyclines; i.e., 330 mg/m2. QT dispersion of the patients and the controls was 0.054±0.02 and 0.05± 0.02 seconds, respectively. No significant difference was found between the patients and the controls regarding corrected QT dispersion (P> 0.05). However, P dispersion time had increased in the patients' group. Our study showed that the duration of anthracyclines therapy did not cause any significant increase in ventricular re-polarization parameters. Conclusion Anthracyclines may show their cardiac toxicity through increasing P dispersion.07/2014; 4(3):103-8.
- "Delivery of densified R-CHOP in older patients with heartrelated morbidities, may however, be challenging because of the acute, early and late cardiotoxicities of doxorubicin (Grann et al, 2006; Hershman et al, 2008). Prolongation of the QTc interval, arrhythmias, myopericarditis and increase of N-terminal (NT)-pro brain natriuretic peptide (proBNP), an early biomarker of ventricular dysfunction, were described during CHOP-like programmes, independently of the cumulative doxorubicin dosing (Elliott, 2006; Johnson, 2006). In general, the suggestion that fit patients with DLBCL, even if aged more than 80 years, should be evaluated for 'adapted' anthracycline-based regimens with curative intent (Bairey et al, 2006; Peyrade et al, 2010; Thieblemont et al, 2008) has to face the problem of cardiac risk factors and comorbidities. "