The cardiotoxicity of anthracyclines is a major problem in cancer chemotherapy, and its alleviation would improve the life expectancy of cancer patients. Doxorubicin dxr is a 14hydroxylated version of daunorubicin, the immediate precursor of dxr in its biosynthetic pathway. Cardiotoxicity of pentavalent antimonials is not new but continues to be reported 10 c. Adriamycin doxorubicin hydrochloride is an antineoplastic agent effective against a wide range of malignant conditions, although cardiac toxicity, especially dosedependent cardiomyopathy, limits its longterm use. Doxorubicininduced cardiotoxicity in adult indian patients. Risk factors and prevention of cardiotoxicity induced by 5. Even if there is a significant sex difference in incidence of cardiovascular disease at the adult stage, it is not known whether a difference in doxorubicin related cardiotoxicity between men and women also exists. Transgenic mice and normal controls 7 weeks old, without regard to sex because our preliminary studies showed no difference in cardiac toxic responses to doxorubicin between males and females were injected intraperitoneally with doxorubicin hydrochloride sigma at 20 mgkg. Nebivolol effect on doxorubicin induced cardiotoxicity in breast cancer flavia cochera, daniel dinca, diana aurora bordejevic, ioana mihaela citu, adelina marioara mavrea, minodora andor, mihai trofenciuc, mirela cleopatra tomescu cardiology department, victor babes university of medicine and pharmacy, timisoara, romania these authors contributed equally to this work purpose. Anthracycline therapy is associated with an increase in the risk for developing heart failure with significant associated morbidity and mortality 1. Anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. This article is from frontiers in pharmacology, volume 5. Polyphenols, autophagy and doxorubicininduced cardiotoxicity.
The exact pathogenesis of doxinduced cardiotoxicity remains to be fully elucidated. Doxil was compared to nonliposomal doxorubicin adriamycin in rabbits and dogs treated i. However, the clinical use of dox is limited by its unwanted cardiotoxicity. Cardiotoxicity definition of cardiotoxicity by medical. Severe cardiotoxicity limits the use of doxorubicin in cancer treatment. This study shows that vascular endothelial growth factorb vegfb gene therapy can be used to prevent the cardiotoxicity of doxorubicin dox. Several other strategies have also been developed 17 in order to reduce the cardiotoxic effects associated with anthracyclines. Doxorubicin dox is a cytotoxic anthracycline antibiotic and one of the important chemotherapeutic agents for different types of cancers. Review of cardiotoxicity among 668 patients treated with 5fu or capecitabine for gastrointestinal cancers. In april and may 2000, an outbreak of fatal cardiotoxicity occurred in nepal amongst patients with visceral leishmaniasis who were treated with a recently introduced batch of generic sodium stibogluconate. The incidence of acute cardiotoxicity is approximately 11% 3,4. This may cause apoptosis of cardiac cells or immunologic reactions. Munas msc research thesis, titled the role of p90 ribosomal s6 kinase and autophagy in sunitinib and ponatinibinduced cardiotoxicity, investigated the cardiotoxic effects associated with ponatinib and sunitinib, small molecules tyrosine kinase inhibitors, used for various types of cancer. Although multiple mechanisms are involved, generation of free radicals is the most commonly.
Nov 22, 2012 currently, there are no guidelines developed specifically for the treatment of chemotherapyinduced cardiotoxicity, however a few small studies support the use of neurohormonal antagonists in the treatment and prevention of this pathology. Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. Molecules free fulltext mitochondriatargeting small. This book intends to bring forward the recent development in toxicities from cancer treatment. Mitochondrial dysfunction has been associated with doxinduced cardiotoxicity.
We prospectively evaluated incidence, time of occurrence, clinical correlates, and response to heart failure therapy of cardiotoxicity. N2 cardiotoxicity is a major side effect of various antineoplastic agents, particularly the anthracyclines. Doxorubicin is associated with cardiotoxicity in 326 % of treated patients, trastuzumab in 228 % and sunitinib in 2. Cardiotoxicity was compared in 21 patients receiving doxorubicin intravenously over 48 or 96 hours and in 30 control. New developments in anthracyclineinduced cardiotoxicity. Early diagnosis and prediction of anticancer druginduced.
However, very few studies have reported incidence of cardiac dysfunction in patients on chemotherapy with lower cumulative doses. The authors declare that they have no conflict of interest. Doxorubicin, whose doselimiting toxicity is cardiomyopathy, was given to four cancer patients. The relative cardiotoxicity of pegylated stealth liposomal doxorubicin pldox.
Early detection of anthracycline cardiotoxicity and. The first session of the international colloquium on cardiooncology rome, march 1214, 2014 asked a provocative question, what is cardiotoxicity. Esmo elearning cardiotoxicity in oncology practice oncologypro. Therapeutic options for this patient group are limited to standard heart failure medications with the only drug specific for doxorubicin cardiotoxicity to reach fda.
Download fulltext pdf anthracycline chemotherapy and cardiotoxicity article pdf available in cardiovascular drugs and therapy 311 february 2017 with 376 reads. The mechanisms of ant cardiotoxicity have been the subject of considerable controversy, and dozens of various potential pathways have been proposed and studied 1, 7, 17, 35, 53, 59, 93, 95, 110, 120, 140, 163. Antioxidants free fulltext liposomal resveratrol and. As a result of cardiotoxicity, your heart may not be able to pump blood throughout your body as well. However, cardiotoxicity is one of the lifethreatening side effects of doxorubicin based therapy. Ferranscomparison of the protective effects against chronic doxorubicin cardiotoxicity and the rates of iron iii displacement reactions of. Three types of anthracyclineinduced cardiotoxicities are currently recognized. The manifestations are usually chest pain due to myopericarditis andor palpitations due to sinus tachycardia, paroxysmal nonsustained supraventricular tachycardia and premature atrial and. Reduction of doxorubicin cardiotoxicity by prolonged. Cardiotoxicity may be caused by radiotherapy andor anticancer agents for many malignancies, adverse effects of some drugs in the context of medical intervention or heavy metal intake, especially during the anticancer therapy. Modulation of doxorubicininduced cardiotoxicity by. Other antioxidants that act following the formation of free radicals have not shown any effectiveness in mitigating anthracyclineinduced cardiotoxicity dzr has.
Pdf doxorubicininduced cardiotoxicity in adult indian. During chemotherapy, you are given toxins drugs to kill cancer cells. Doxorubicin cardiotoxicity is associated with the generation of free radicals, and involves not only lipid. Chemical structures of the anthracycline antibiotics daun a and 5id b.
Cardiotoxicity induced by antineoplastic drugs is becoming an. The heart becomes weaker and is not as efficient in pumping and therefore circulating blood. However, role of antioxidants in cancer therapy are controversial. Our results provide insights into the molecular basis for the different cardiotoxicity of the two drugs, as well as the importance of the quinone structure to the observed effects. The cardiotoxicity of doxorubicin is becoming an interdisciplinary point of interest given a growing population of cancer survivors. Reduced cardiotoxicity of doxorubicin delivered on a weekly schedule. Use of myocardial strain imaging by echocardiography for the. Pdf new developments in anthracyclineinduced cardiotoxicity. The molecular basis for doxorubicin cardiotoxicity and the. Free radical formation has been implicated in doxorubicin cardiotoxicity by means of cu ii and fe iii reduction at the cellular level. Ifosfamide ifs is a new alkylating oxazaphosphorine related to cyclophosphamide. Cardiotoxicity is defined as any heart injury functional or structural related to cancer treatment, taking into consideration chemotherapy, radiotherapy and cancer itself. We report for first time acute cardiac side effects upon ifs treatment in the form of supraventricular arrhythmias and stt wave changes.
Novel diagnostic tools might be relevant to early recognize irreversible forms cardiac. Cardiotoxicity of anticancer treatments is associated with development of heart failure. Genetic determinants contributing to this variation are difficult to study using current mouse models. Doxorubicin induced cardiotoxicity is widely known to occur at cumulative doses exceeding 450 mgm2. Doxorubicin dox, or adriamycin, an anthracycline antibiotic discovered serendipitously as a chemotherapeutic drug several decades ago, is still one of the most effective drugs for treating various adult and pediatric cancers breast cancer, hodgkins disease, lymphoblastic leukemia. However, data supporting this classification are lacking. Doxorubicin induced cardiotoxicity in adult indian patients on chemotherapy. Pdf antineoplastic drugs can be associated with several side effects, including cardiovascular toxicity ctx.
It updates the possible mechanisms of cardiotoxicities of some anticancer. Cardiotoxicity is the occurrence of heart electrophysiology dysfunction or muscle damage some drugs may affect the heart as toxic effects,then heart becomes weaker and is not as efficient in pumping it is the major concern during drug development, with increased pro arrhythmic potential being the main culprit 2. Vegfb inhibited doxinduced cardiac atrophy, protected endothelial cells from. This retrospective study aimed to identify risk factors and to give practical measures to make such chemotherapy feasible if cardiotoxicity occur. To mitigate doxrelated cardiotoxicity, considerable successful examples of a variety of small molecules that target mitochondria to modulate. From molecular mechanisms to therapeutic strategies. Although combination of trastuzumab and anthracyclinebased chemotherapy, such as doxorubicin, is used as a standard of care in the treatment for patients at different stages of breast cancers, understanding of the mechanisms of cardiotoxicity. Preventing the cardiotoxic effects of anthracyclines. Pdf 20090831 19 17 dw c documents and settings nick application data reg tool connect your phone to computer and launch software 20100127 03 53 dw c program files norton support middle tier to validate the input and output. Other agents that may induce a cardiac event include paclitaxel, etoposide, teniposide. Cardiotoxicity is a common complication of chemotherapy. Two approaches for primary prevention of anthracyclineinduced cardiotoxicity are.
Herein, human serum albumin hsa is engaged as a biocompatible nanocarrier to load a phsensitive dox prodrug, dmdox, generating hsadmdox. Create a free personal account to download free article pdfs, sign up for alerts, customize your interests. Free radicals mainly nitrite free radicals are the. We used the pubmed database to identify relevant studies published through december 28, 2014. Tricyclic antidepressant cardiotoxicity jama jama network. Cardiotoxic definition of cardiotoxic by medical dictionary. Sexual dimorphism of doxorubicinmediated cardiotoxicity. Doxorubicininduced cardiotoxicity in collaborative cross. Both of these studies emphasize the critical role of iron in the pathogenesis of doxorubicin induced cardiotoxicity. Clinical data clinical features of anthracycline cardiotoxicity.
Strategies to prevent anthracyclineinduced cardiotoxicity in cancer. Doxorubicin and daunorubici n differ in their short chains. Doxorubicin is among the most effective and widely used anticancer drugs in the clinic. This study examined the cardioprotective effects of carvedilol car andor resveratrol res and liposomal res lipores against doxinduced cardiomyopathy, pointing to. The aim of this study was to assess the cardiotoxicity of anticancer drugs using tissue doppler imaging. Although we are going to focus on myocardial damage, cardiotoxicity also produces other heart affections, including pericardial, valvular or coronary artery diseases. Doxorubicin toxicity involves the generation of reactive oxygen species ros and hence several antioxidants and plant products have been tried to minimise the cardiotoxicity. Our objective was to determine whether a spectrum of anthracycline induced cardiac disease can be elicited across 10 collaborative cross mouse strains given the same dose of doxorubicin. Attenuation of doxorubicininduced cardiotoxicity by mdivi. Doxorubicin operates on several levels by different molecular mechanisms including an interaction with iron, upsetting calcium homeostasis, altering the activity of intracellular or intramitochondrial oxidant enzymes, and binding to.
Cardiotoxicity induced by antineoplastic drugs is becoming an important health. Eligible studies included randomized controlled trials directly comparing the efficacy and cardiotoxicity of liposomal doxorubicin based chemotherapy with conventional doxorubicin in advanced breast cancer with adequate data. Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes. Preclinical mechanisms and clinical correlates of cardiotoxicity are pillars of contemporary cardiooncology. No histological evidence of cardiotoxicity was seen in dogs treated with placebo liposomes or pldox every 3 weeks for a total of 10 doses cumulative doxorubicin dose 10 mgkg either 1 or 5. Nevertheless, the ironmediated formation of ros and promotion of myocardial oxidative stress remain by far the most frequently proposed mechanism. Abstractthe clinical use of the antitumor anthracycline doxorubicin is limited by the risk of severe. The mechanism of anthracycline induced cardiotoxicity seems to involve the formation of free radicals leading to oxidative stress. Cardiotoxicity, pharmacokinetics and therapeutic use of anthracyclines. Reduction of the cardiotoxicity of doxorubicin in rabbits. No studies have investigated the effects of cr alone or the combined effects of cr and exercise on dox cardiotoxicity.
Other than for strictly personal use, it is not permitted to download or to forwarddistribute the text or part of it. Nebivolol effect on doxorubicininduced cardiotoxicity in. Unfortunately, their efficacy in treating cancer is limited by a cumulative dosedependent cardiotoxicity, which can cause irreversible heart failure. Dox treatment is associated with adverse effects, particularly cardiac dysfunction. Propolis doxorubicin cardiotoxicity antioxidant pdf downloadpropolis doxorubicin cardiotoxicity antioxidant pdf. Pdf update on cardiotoxicity of anticancer treatments. Doxorubicin dox is a widely used chemotherapeutic agent with known cardiotoxic properties, while calorie restriction cr and exercise have welldocumented cardioprotective effects. The complex and not completely understood pathogenesis of this complication makes difficult to design successful preventive or curative measures. Cardiotoxicity and cardiomyopathy managing side effects.
Dosedependent cardiotoxicity of doxorubicin may lead to irreversible congestive heart failure. Previous studies have also shown doxorubicin to cause cardiotoxicity through the generation of free radicals 5, stimulation of lipid peroxidation 6 and alteration and disruption of cellular membrane integrity 7. Cancer treatmentrelated cardiotoxicity includes efforts to identify individual toxicity risks and prevention strategies support the national cancer insitutes goal of reducing the burden of cancer diagnoses and treatment outcomes. Dexrazoxane is an iron chelator that binds free iron or. Efficacy and cardiotoxicity of liposomal doxorubicinbased. Doxorubicin cardiotoxicity and melphalan annals of. Endomyocardial biopsy specimens and test results of cardiac function were obtained before, during, and after treatment. The clinical use of doxorubicin, widely used as an antineoplastic agent, is markedly hampered by severe cardiotoxicity. Monitoring for chemorelated cardiotoxicity b k tamarappoo, md, phd codirector, cardiooncology center section of cardiovascular imaging department of cardiovascular medicine.
Dexrazoxane zinecard, also known as icrf187 has been used in the clinic as a cardioprotectant against doxorubicin cardiotoxicity. Large, multicenters trials are needed to establish guidelines for chemotherapyinduced cardiotoxicity. Randomized trial of lisinopril versus carvedilol to prevent trastuzumab cardiotoxicity in patients with breast cancer maya guglin, pamela n. Doxorubicin hydrochloride for injection, usp patient. Cardiotoxicity was monitored by noninvasive methods, and endomyocardial biopsy specimens were studied by electron microscopy. Three forms of anthracycline cardiotoxicity are described. Overview of studies examining the roles of oxidative stress and free cellular iron. It also showed a higher therapeutic index, yet the cardiotoxicity remained. Derivation of anthracycline and anthraquinone equivalence. Doxorubicin is a commonly used chemotherapeutic agent for the treatment of a range of cancers, but despite its success in improving cancer survival rates, doxorubicin is cardiotoxic and can lead to congestive heart failure. The cause of doxinduced cardiotoxicity is multifactorial and includes free radicalinduced.
Cardiotoxicity of doxorubicin and other anthracycline. Doxorubicin showed better activity than daunorubicin against mouse tumors, and especially solid tumors. Doxorubicin induced cardiotoxicity can also result from the activation of innate and adaptive immunity. Potentiation of doxorubicin cardiotoxicity by iron loading. Cytostatic antibiotics of the anthracycline class are the best known of the chemotherapeutic agents that cause cardiotoxicity. Doxorubicin induces cardiotoxicity through upregulation of. Cardiotoxicity is a wellknown side effect of several cytotoxic drugs, especially of the anthracyclines and can lead to long term morbidity. They cause redox reactions through formation of cytotoxic free radicals. The role of ampk activation for cardioprotection in. Effects of calorie restriction and voluntary exercise on. T1 prevention and management of cardiotoxicity from antineoplastic therapy.
Cardiotoxicity associated with anthracyclinebased chemotherapies has limited their use in. In addition to traditional mediators of myocardial damage, such as reactive oxygen species, new pathways and target cells should be considered responsible for the impairment of cardiac function during. Jul 14, 2015 although treatment for heart failure induced by cancer therapy has improved in recent years, the prevalence of cardiomyopathy due to antineoplastic therapy remains significant worldwide. Cardiotoxicity is a condition when there is damage to the heart muscle. Cancer treatmentrelated cardiotoxicity egrpdccpsncinih. Iron chelators and free radical scavengers may provide cardiac protection by preventing the formation of the reactive hydroxyl radical and by scavenging radicals that have been formed. A sideeffect is that the normal cells in and around your heart can also be killed. Alkylating agents such as cyclophosphamide, ifosfamide, cisplatin, carmustine, busulfan, chlormethine and mitomycin have also been associated with cardiotoxicity. The iron chelator icrf187 has been shown to protect against doxinduced cardiotoxicity. Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats. Pdf the clinical use of doxorubicin and other quinonehydroquinone anticancer anthracyclines is limited by a doserelated cardiotoxicity. The anticancer drug doxorubicin dox also referred to as adriamycin is highly effective in the treatment of a broad range of cancers. Teaching the basics of the mechanism of doxorubicin. Pdf doxorubicin induced cardiotoxicity is widely known to occur at cumulative doses exceeding 450 mgm2.
Doxorubicin, also known as adriamycin or rubex, is an anthracycline antibiotic that was discovered from a mutated strain of streptomyces peucetius. However, very few studies have reported incidence of cardiac dysfunction in patients on. The use of anthracyclines is limited by dosedependent cardiotoxicity. Although cardiomyocyte has been considered a classical cellular target, other cells including various types of. Daunorubicin is more abundantly found as a natural product because it is produced by a number of different wild type strains of streptomyces. The anthracyclines and related compounds doxorubicin, daunorubicin, idarubicin, epirubicin, and the anthraquinone mitoxantrone are among the chemotherapeutic agents implicated in cardiotoxicity. Doxorubicin dox is a chemotherapeutic agent widely used for the treatment of numerous cancers. Access to this free content requires users to be registered and logged in. Subsequent research has led to many other anthracycline. Reduced cardiotoxicity of doxorubicin delivered on a. Doxorubicin cardiotoxicity can be acute, occurring during and within 23 days of its administration.