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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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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ABSTRACT: Background: Anthracycline-induced cardiotoxicity can result in acute, sub-acute and chronic complications, which can lead to cardiomyopathy and heart failure. The mortality and morbidity are increased in patients who have anthracycline-induced cardiotoxicity. A few previous studies have demonstrated the efficacy of some agents in preventing cardiotoxicity from anthracycline. Objectives: To assess the efficacy of an angiotensin II receptor blocker (candesartan), in preventing anthracycline-induced cardiotoxicity, and to evaluate the side effects of candesartan in cancer-patients who received doxorubicin. Methods: Consecutive patients who were scheduled for treatment with doxorubicin from March 1, 2009 to January 31, 2010 were recruited. Breast cancer or lymphoma patients, who had definite coronary artery disease (CAD), left ventricular (LV) dysfunction; chronic kidney disease (CKD) and hyperkalemia were excluded. Patients were randomized into two groups; the first group received candesartan 4-32 mg daily while the second group did not (controls group) until the end of the anthracycline regimen. Baseline echocardiographic parameters were measured and followed up after 3 courses of anthracycline administration. The changing of echocardiographic parameters, serum potassium levels and serum creatinine levels were recorded and analyzed. Results: There were 21 patients enrolled. The mean age of the candesartan group was 51.1 ± 11.31years, and 54.20 ± 10.21 years for the control group (p=0.528). No significant changes were observed in blood pressure and heart rate between the two groups. There were significant increases in potassium and creatinine levels in the candesartan group (p= 0.001 and 0.001, respectively). There was a significant difference in left ventricular ejection fraction (LVEF) at the end of the study between the candesartan and control group (67.10 ± 6.12% and 62.60 ± 7.75% respectively, p= 0.023). There was a significant decrease in LVEF (69.00 ± 8.82% and 62.60 ± 7.75%, p=0.03) from the baseline to the half course of chemotherapy in the control group. There was no significant change in LVEF observed in the candesartan group. Conclusion: These results indicate that candesartan may have a potential in preventing the anthracycline-induced cardiotoxicity in cancer patients. It increases serum potassium levels and creatinine levels but does not induce hyperkalemia or acute kidney injury. Future long-term and larger population studies are necessary.
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ABSTRACT: In the search for new therapeutic alternatives against cancer, either as a preventive treatment or for advanced stages, it is common to appeal to well-known drugs used for the treatment of other diseases that may interfere with the metabolic pathways involved in carcinogenesis. Non-steroidal anti-inflammatory drugs (NSAIDs) display anticancer activity through the inhibition of the COX-2 enzyme, triggering processes such as apoptosis, a reduction in proliferation and inhibition of carcinogenesis. Breast cancer is a neoplasm with the highest incidence and mortality rate among young women worldwide. Epidemiologic data have shown that drugs such as NSAIDs, particularly aspirin, reduce the relative risk of breast cancer. However, in the subgroup of responsive patients, dose, time and frequency of use have not yet been established. Here, we review the reports published during the last 10 years regarding the relationship between breast cancer and aspirin.Oncology reports. 06/2014;