Anthracycline-induced cardiotoxicity

Anthracycline antibiotics are among the most effective and widely used antineoplastic drugs. Their usefulness is limited by a cumulative dose-related cardiotoxicity, whose precise mechanisms are not clear as yet. The principal role is possibly exerted by free oxygen radicals generated by "redox-cycling" of anthracycline molecule and/or by the formation of anthracycline-ferric ion complexes. The iron catalyzes the hydroxyl radical production via Haber-Weiss reaction. The selective toxicity of ANT against cardiomyocytes results from high accumulation of ANT in cardiac tissue, appreciable production of oxygen radicals by mitochondria and relatively poor antioxidant defense systems. Other additional mechanisms of the anthracycline cardiotoxicity have been proposed--calcium overload, histamine release and impairment in autonomic regulation of heart function. The currently used methods for an early identification of anthracycline cardiotoxicity comprise ECG measurement, biochemical markers, functional measurement and morphologic examination. Among a plenty of studied cardioprotective agents only dexrazoxane (ICRF-187) has been approved for clinical use. Its protective effect likely consists in intracellular chelating of iron. However, in high doses dexrazoxane itself may cause myelotoxicity. This fact encourages investigation of new cardioprotectants with lower toxicity. Orally active iron chelators and flavonoids attract more attention. Modification of dosage schedule and synthesis of new anthracycline analogues may represent alternative approaches to mitigate anthracycline cardiotoxicity while preserving antitumour activity.     

Melatonin protects against epirubicin-induced cardiotoxicity

We investigated the cytoprotective effect of melatonin in epirubicin-induced cardiotoxicity using four experimental groups of male Wistar rats: untreated control rats, epirubicin-treated rats, epirubicin+melatonin-treated rats, and melatonin-treated rats. We examined the histopathological and biochemical effects of melatonin on the epirubicin-induced changes and measured the levels of the lipid peroxidation end-product (malondialdehyde, MDA), an indicator of nitric oxide (NO) synthesis (nitrite/nitrate production), and reduced glutathione (GSH) in the heart. We also studied the extracellular matrix components (fibronectin, laminin) in the heart. Vacuole formation, mitochondrial deformation and degeneration, and disordered myofibrillary structures were detected ultrastructurally in the epirubicin-treated group. The degeneration was reduced in the heart tissues of the epirubicin+melatonin group. Epirubicin increased the nitrite/nitrate production, but did not change the MDA and GSH levels significantly. Melatonin treatment lowered the nitrite/nitrate concentrations, while increasing the GSH levels, which exceeded the levels in epirubicin+melatonin-treated rats. We conclude that the epirubicin increased the nitrozative stress, not the oxidative stress, in heart tissue, and the cardioprotective effect of melatonin was partially attributed to the suppression of epirubicin-induced nitrozative stress. These results suggest that melatonin partially protects against epirubicin-induced cardiotoxicity.     

Cardiomyocyte death in doxorubicin-induced cardiotoxicity

Doxorubicin (DOX) is one of the most widely used and successful antitumor drugs, but its cumulative and dose-dependent cardiac toxicity has been a major concern of oncologists in cancer therapeutic practice for decades. With the increasing population of cancer survivors, there is a growing need to develop preventive strategies and effective therapies against DOX-induced cardiotoxicity, in particular late-onset cardiomyopathy. Although intensive investigations on DOX-induced cardiotoxicity have continued for decades, the underlying mechanisms responsible for DOX-induced cardiotoxicity have not been completely elucidated. A rapidly expanding body of evidence supports the notion that cardiomyocyte death by apoptosis and necrosis is a primary mechanism of DOX-induced cardiomyopathy and that other types of cell death, such as autophagy and senescence/aging, may participate in this process. This review focuses on the current understanding of the molecular mechanisms underlying DOX-induced cardiomyocyte death, including the major primary mechanism of excess production of reactive oxygen species (ROS) and other recently discovered ROS-independent mechanisms. The different sensitivities to DOX-induced cell death signals between adult and young cardiomyocytes will also be discussed.     

Doxorubicin cardiotoxicity in African Americans

PURPOSE: The African-American race was examined as a risk factor for cardiotoxicity from doxorubicin-based therapy for cancer. PATIENTS AND METHODS: Retrospective survey of the Howard University Hospital cancer registry during 1997-2001 identified 100 evaluable patients out of 120 African Americans who underwent doxorubicin-based combination chemotherapy (65% women, 35% men, median age 46 years, range 32-84 years). The fraction of patients who developed post-treatment cardiotoxicity, defined as congestive heart failure or a left-ventricular ejection fraction less than 45%, was compared with that from a retrospective study of 399 patients of unknown age and racial distribution. Cases were stratified by cumulative dose of doxorubicin. Statistical significance of the difference in incidence of cardiotoxicity was tested by chi-square analysis. RESULTS: Patients received multiple doses of doxorubicin (range 264 to 580 mg/m2 with median of 374) with the final echocardiographic assessment at a median of 1.3 years. Howard oncologists frequently used a 48-hour infusion rather than the conventional rapid bolus to reduce the cardiotoxicity of doxorubicin. The fraction with cardiotoxicity in our study versus Lefrak's review at four ranges of doxorubicin was 25% versus 18% at 551-600 mg/m2, 10% versus 4% at 501-550 mg/m2, 4% versus 1% at 451-500 mg/m2, and 0% versus <1% at <450 mg/m2. Seventy-two percent of the patients having depressed ejection fraction and/or heart failure were women. African Americans had a higher rate of cardiotoxicity after doxorubicin (7/100 cases) than that of Lefrak's (10/399) study population and were statistically significant at p<0.027 with an odds ratio of 2.93. CONCLUSION: We have shown for the first time that African Americans at our institution appear to suffer cardiotoxicity from doxorubicin three times more frequently than the previously noted study population. To better clarify this observation, a larger study in a multiracial setting is needed.     

Combined cardiotoxicity of adriamycin and x-radiation.

Our previous studies have shown that x-radiation produces cardiac lesions. Likewise, adriamycin, a useful antineoplastic agent, is known to be cardiotoxic. Maximal "safe" doses have been established for each of these forms of therapy. Since combined therapy with adriamycin and radiation is being used for malignancies involving the mediastinum, it is important to know whether the combination of both agents is more cardiotoxic than either agent alone. In this study young New Zealand White rabbits were divided into five groups and given: (1) a single dose of x-radiation of 1600 rads in the cardiac area; (2) 167 mg. per sq. m. of adriamycin; (3) both raddiation and adriamycin at the same doses; (4) 255 mg. per sq. m. of adriamycin; (5) no treatment. Animals in the third (combined) group developed radiation and adriamycin lesions, the frequency and severity of which were greater than those in the single therapy groups at the same (low) doses. These observations suggest a synergistic effect of the two agents. If so, patients receiving combined treatment are at risk of developing severe carditis from doses of adriamycin and cardiac x-radiation today regarded as safe. Although neither one is specific, the light and electron microscopic lesions caused by x-radiation (myocardial capillary damage, pericarditis) were easily distinguished from those caused by adriamycin (myocyte damage). Both agents led to diffuse myocardial fibrosis. These morphologic characteristics may have clinical applications.     

磷酸肌酸钠对阿霉素所致心肌损伤的影响

目的: 探讨磷酸肌酸钠对阿霉素所致小鼠心肌损伤的保护作用及机制。方法: 60只雌性BALB/c小鼠随机分为磷酸肌酸钠干预组、阿霉素组和正常对照组,观察小鼠的一般情况,检测血清中肌钙蛋白I(TnI)、N端前脑钠肽(NT-proBNP)及心肌组织中丙二醛(MDA)、ATP酶的变化,心肌细胞凋亡及心肌组织 bcl-2、fas 基因的表达。结果: 与对照组及磷酸肌酸钠组比较,阿霉素组心肌细胞发生明显的水肿变性,并可见部分细胞凋亡,凋亡指数增大(P<0.05);阿霉素组MDA明显增高 (P<0.05),ATP酶活力降低(P<0.05);血清中TnI和NT-proBNP有增高的趋势(P＞0.05);磷酸肌酸钠组与阿霉素组比较, bcl-2 基因表达增多,fas基因表达减少(P<0.05)。结论: 磷酸肌酸钠对阿霉素所致的心肌损伤具有保护作用,其机制可能与磷酸肌酸钠减少氧自由基和抑制细胞凋亡有关。     

6-Hydroxydopamine mediated cardiotoxicity in rabbits

Weekly injections of the catecholamine depleting agent 6-hydroxydopamine (6-OHDA) were used to denervate rabbit hearts chemically. Analyses of morphology and beta-adrenergic receptor density were made at 1, 2, and 4 weeks. Changes resulting from subacute and chronic inflammatory processes were evident by light microscopy after 1 week. At that time, electron microscopy revealed marked increases in collagen, large myocytic vacuolizations in myocytes, widened gap junctions, and myofibrillar degeneration and dropout. Receptor density was marginally increased at 2 weeks but was decreased (p less than .05) at 4 weeks (maximal [3H]dihydroalprenolol (DHA) binding in fmol/mg: 69.6 +/- 5.4 in controls vs 49.2 +/- 5.1 in 6-OHDA-treated animals). Basal, isoproterenol-stimulated and F- -stimulated adenylate cyclase activities were decreased in the 6-OHDA-treated group at 4 weeks. We conclude that administration of 6-OHDA may cause severe myocardial damage, and that this process may involve loss of some functional components of the cell membrane.     

Molecular basis of anthracycline-induced cardiotoxicity and its prevention

Anthracyclines are a class of highly potent antitumor antibiotics utilized against hematologic and solid tumors in children and in adults. Their use has been limited primarily by their cardiotoxic side effects, which may lead to congestive heart failure. Although there is a linear relationship between the cumulative dose received and the incidence of cardiotoxicity, in some patients cardiotoxicity may develop at doses below the generally accepted threshold level. Anthracycline-induced cardiotoxicity is believed to be related to the generation of highly reactive oxygen species, which, by means of membrane lipid peroxidation, cause direct damage to cardiac myocyte membranes. Another important factor may be the relatively poor antioxidant defense system of the heart. In an attempt to circumvent these toxic effects, a wide variety of antioxidants have been used in cell culture, animal, and human studies without consistent beneficial effects. Moreover, none of the agents used to date are designed to act selectively upon the heart. If the cardiac complications resulting from anthracyclines could be reduced and/or prevented, higher doses could potentially be used, thereby increasing cancer cure rates. Furthermore, the incidence of cardiac toxicity resulting in congestive heart failure or even heart transplantation would be reduced, therefore increasing the quality and extent of life for cancer survivors. This article will review the basic science of free radical biology, the biology of oxygen-derived free radicals and antioxidant proteins, and explore some new and innovative approaches to limiting and/or preventing anthracycline-induced cardiotoxicity.     

黄酒多酚减轻阿霉素心脏毒性的初步研究

目的:探讨黄酒多酚化合物(YWPC)减轻阿霉素(即多柔比星,DOX)所致心脏毒性的作用及其机制。方法:将40只雄性SD大鼠随机分成4组:对照组、YWPC组、DOX组和DOX+YWPC组。干预4周后,超声心动图检测大鼠心功能;病理学染色观察心脏组织病理学改变;比色法、DHE染色、TUNEL染色和Western blot法检测心肌组织中心肌酶、氧化应激和凋亡水平的改变。结果:与对照组相比,DOX组左室射血分数(LVEF)和左室短轴缩短分数(LVFS)明显下降,而收缩期左室内径(LVIDs)和舒张期左室内径(LVIDd)明显增加;而与DOX组相比,DOX+YWPC组LVEF和LVFS增加,LVIDs和LVIDd下降(P 0. 05)。DOX组血清心肌损伤指标乳酸脱氢酶(LDH)、肌酸激酶(CK)、天冬氨酸转氨酶(AST)和心肌肌钙蛋白I(c Tn I)较对照组明显增加;而DOX+YWPC组上述指标较DOX组下降(P 0. 05)。与对照组比较,YWPC组无明显病理学改变,DOX组出现心肌纤维排列紊乱、细胞核溶解和肌纤维解体,而DOX+YWPC组上述情况明显改善。与对照组比较,DOX组活性氧簇(ROS)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)和谷胱甘肽(GSH)水平下降,丙二醛(MDA)水平增加;与DOX组相比,DOX+YWPC组上述指标均得到逆转(P 0. 05)。同时,DOX组较对照组心肌细胞凋亡水平、Bax/Bcl-2比和cleaved caspase-3水平增加,而DOX+YWPC组心肌细胞凋亡明显受到抑制(P 0. 05)。结论:黄酒多酚可以通过减少氧化应激和抑制心肌细胞凋亡拮抗阿霉素所致的心脏毒性。     

Direct cocaine cardiotoxicity demonstrated by endomyocardial biopsy

The morbidity and mortality associated with cocaine abuse has markedly increased in recent years. Although several articles indicate a possible connection of cocaine with coronary spasm and acute myocardial infarction, this study in seven patients with a history of cocaine abuse, who underwent endomyocardial biopsy, suggests that cocaine may cause direct toxicity to the myocardium. Myocardial specimens from five of seven patients showed multifocal myocyte necrosis, of which two specimens revealed focal myocarditis, while three specimens had changes consistent with dilated cardiomyopathy. Ultrastructurally, extensive loss of myofibrils and sarcoplasmic vacuolization were observed. It is postulated that the pathogenesis of acute cocaine-induced toxicity is direct destruction of myofibrils resulting in myocyte necrosis and that these changes may or may not be associated with interstitial inflammatory cell infiltrates. Long-term abuse of cocaine may lead to interstitial fibrosis and eventually congestive heart failure.     

A multifaceted evaluation of imatinib-induced cardiotoxicity in the rat

Cardiotoxicity was an unanticipated side effect elicited by the clinical use of imatinib (Imb). This toxicity has been examined in only a limited number of experimental studies. The present study sought, by a variety of approaches, to identify important characteristics of Imb-induced cardiac alterations. Male spontaneously hypertensive rats (SHRs) received oral doses of 10, 30, or 50 mg/kg Imb or water daily for 10 d. Cardiac lesions, detected at all doses, were characterized by cytoplasmic vacuolization and myofibrillar loss. In a second experiment, cardiac lesions were found in Sprague Dawley (SD) and SHR rats given 50 or 100 mg/kg Imb for 14 d. Mean cardiac lesion scores and serum levels of cardiac troponin I were higher in SHRs than in SD rats. Imb induced myocyte death by necrosis, autophagy, and apoptosis. Dose-related increases in cardiac expression were observed for several genes associated with endoplasmic reticulum stress response, protein folding, and vascular development and remodeling. Imb caused alterations in isolated myocytes (myofibrillar loss, highly disrupted and disorganized sarcomeric α-actinin, apoptosis, and increased lactate dehydrogenase release) at low concentrations (5 mM). The authors conclude that Imb exerts cardiotoxic effects that are manifest through a complex pattern of cellular alterations, the severity of which can be influenced by arterial blood pressure.     

Protective effects of silymarin and curcumin on cyclophosphamide-induced cardiotoxicity

Introduction

Cyclophosphamide (CP) is a potent anticancer agent; its clinical use is limited due to its marked cardiotoxicity.

Abrogation of adriamycin-induced cardiotoxicity by selenium in rabbits.

Adriamycin-induced cardiomyopathy in rabbits was produced by intravenous injections of the drug with a short therapeutic schedule (3 mg/kg body wt administered as four intermittent doses). Animals receiving selenium supplementation of Adriamycin showed preservation of the normal pattern of the heart histologic picture. The protective effect of selenium was accompanied by increased selenium levels in the plasma and the heart muscle. An eventual interaction between the antitumor effect of Adriamycin and the protective effect of selenium was ruled out by in vitro experiments using the L1210 cell line. Selenium did not abrogate the antiproliferative effect of Adriamycin when the cells were treated simultaneously with both agents. The results from this study indicate that Adriamycin-induced cardiotoxicity could be prevented by selenium if the animals were pretreated with selenium, rather than simultaneous administration of both agents. The mechanism of this effect is not entirely understood.