Prevention of anthracyclineinduced cardiotoxicity challenges and opportunities pimprapa vejpongsa, md, edward t. Doxorubicin dox is the predominant anthracycline, but its use is limited due to cardiotoxicity octavia et al. Severe local tissue necrosis will occur if there is extravasation during administration. The comparison of heart tissues of control rats and of rats treated with 20 mgkg dox by electron microscopy revealed massive fragmentation and lysis of the myofibrils upon dox treatment fig. Doxorubicin pi may 8, 2003 1 1 2 doxorubicin hydrochloride for injection, usp 3 4 doxorubicin hydrochloride injection, usp 5 6 rx only 7 8 for intravenous use only 9 10 warning 11 1. Propolis doxorubicin cardiotoxicity antioxidant pdf downloadpropolis doxorubicin cardiotoxicity antioxidant pdf.
Product information adriamycin solution for injection warnings 1. Congestive heart failure in patients treated with doxorubicin. Doxorubicin induces cardiotoxicity in a pluripotent stem. Yeh, mdy abstract anthracycline compounds are major culprits in chemotherapyinduced cardiotoxicity, which is the chief limiting factor in delivering optimal chemotherapy to cancer patients. Oct 01, 2003 the anthracycline, doxorubicin dox, is one of the most widely used and active cytotoxic agents in cancer chemotherapy. Anthracycline chemotherapy and cardiotoxicity john v. Jci insight highly potent visnagin derivatives inhibit. Acute effects occur within 48 h of infusion and are generally reversible and clinically manageable takemura and fujiwara, 2007. From mechanisms to development of efficient therapy. Chemotherapy with doxorubicin is limited by cardiotoxicity. Mitochondria showed either vacuolization or complete loss of the cristae. Doxorubicin, whose doselimiting toxicity is cardiomyopathy, was given to four cancer patients.
Congestive heart failure in patients treated with doxorubicin a retrospective analysis of three trials sandra m. Cardiotoxicity was compared in 21 patients receiving doxorubicin intravenously over 48 or 96 hours and in 30 control. Rutin attenuates doxorubicininduced cardiotoxicity via regulating autophagy and apoptosis. Downloaded from the university of groningenumcg research database pure. From mechanisms to development of efficient therapy find, read and cite all the research. Anthracycline cardiotoxicity remains a serious problem in pediatric and adult cancer survivors. Myocardial damage, including acute left ventricular failure, can occur with doxorubicin hydrochloride. Cardiotoxicity and cardiomyopathy managing side effects. The molecule is amphoteric, containing acidic 66 functions in the ring phenolic groups and a basic function in the sugar amino group. The authors tested the hypothesis that toxicity to dox may be modulated by mutations that result in genetic iron overload. However, the use of doxorubicin is an important clinical problem due to its cardiotoxicity. Background doxorubicin, a commonly used anticancer drug, is known to cause serious and potentially lifethreatening cardiotoxicity. Prevention of cardiotoxicity and future directions. A recent finding indicates the importance of cardiomyocytes apoptosis in doxorubicininduced cardiotoxicity.
Doxorubicin pi may 8, 2003 3 65 sugar, producing a hydrophilic center. The mechanisms of doxorubicininduced cardiotoxicity dic remain incompletely understood. Treatment of diffuse large bcell lymphoma in elderly. Doxorubicin cardiotoxicity and melphalan annals of internal. Currently it is unclear, which of these mechanisms are the most responsible for its associated cardiac toxicity. Research paper mechanism of doxorubicin cardiotoxicity evaluated by integrating multiple molecular effects into a biophysical model correspondencedrstevena. Doxorubicin can be reduced to a semiquinone not depicted by nadph oxidase or enos.
Cardiotoxicity is a wellrecognized side effect of anthracycline therapy that limits the total amount of drug administered and can cause heart. A commonly used anthracycline is called doxorubicin adriamycin. Objectives the role of iron toward doxorubicin dox cardiotoxicity was studied using a rodent model of dietary carbonyl iron loading. Epsteinsuppression of doxorubicin cardiotoxicity by overexpression of catalase in the heart of transgenic mice. Pdf on nov 14, 2018, danubia silva dos santos and others published doxorubicininduced cardiotoxicity. The complex and not completely understood pathogenesis of this complication makes difficult to design successful preventive or curative measures. There are various signalling mechanisms involved in doxorubicin cardiotoxicity. In humans, dox cardiotoxicity manifests over two time scales. Mmp inhibitors attenuate doxorubicin cardiotoxicity by. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Different dosage schedules for reducing cardiotoxicity in people with cancer receiving anthracycline chemotherapy. Although cardiomyocyte has been considered a classical cellular target, other cells including various types of. As a result of cardiotoxicity, your heart may not be able to pump blood throughout your body as well.
The anthracycline doxorubicin dox has proved to be one of the most widely used and most effective antitumor drugs since its emergence in the 1960s. Doxorubicin has been used extensively for the treatment of hematological cancers, cancers of breast, lung and bone, and soft tissue sarcomas. We used the pubmed database to identify relevant studies published through december 28, 2014. Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes. It also showed a higher therapeutic index, yet the cardiotoxicity remained. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a pdf plugin installed and enabled in your browser. Pdf on nov 14, 2018, danubia silva dos santos and others published doxorubicin induced cardiotoxicity. Get a printable copy pdf file of the complete article 883k. Several liposomal formulations of doxorubicin are in use, having the benefits of prolonging retention rate while reducing peak plasma concentration of free drug.
Severe local tissue necrosis will occur if there is extravasation during administratio. Contemporary treatment methods, such as tyrosine kinase inhibitors, anthracycline. Doxorubicin and daunorubicin can cause dosedependent cardiomyopathy in children and adults 1, 2. Data was collected on patients who received 90 mgm 2 doxorubicin as a continuous infusion and 10 gm. The drug should be administered under the supervision of an experienced cancer chemotherapy physician. Despite the dosedependent response rate of sarcomas to doxorubicin, clinicians limit its cumulative dose due to cardiotoxicity.
In this study, we explored the protective role of rutin on doxorubicin induced heart failure and elucidated the potential mechanisms of protective effects of rutin against cardiomyocyte death. Rutin attenuates doxorubicininduced cardiotoxicity via. We determined in mice whether matrix metalloproteinase2, an intracellular and extracellular protease in the heart, contributes to doxorubicin cardiotoxicity. Reduction of doxorubicin cardiotoxicity by prolonged. Alternatively, you can download the file locally and open with any standalone pdf reader. Cells treated with doxorubicin have been shown to manifest the characteristic morphologic changes associated with apoptosis or programmed cell death. Mar 16, 2017 doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes. Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive b cell lymphoma cancer patients.
A read is counted each time someone views a publication summary such as the title, abstract, and list of authors, clicks on a figure, or views or downloads the fulltext. Druk dx pam644 item code pfizer perth pty limited, australia. Thomas hospital, westminster bridge road, london se1 7eh, uk. Doxorubicin is a highly efficacious anticancer drug but causes cardiotoxicity in many patients. Ironing out doxorubicinrelated cardiotoxicity blood. Risk factors that predispose patients to cardiomyopathy include advanced age, previous radiotherapy to the mediastinum, and concurrent cyclophosphamide therapy 2. Download acrobat pdf file 8mb transparency document. Early evidence of cardiotoxicity and tumor response in. Doxorubicin and daunorubici n differ in their short chains. Doxorubicin hydrochloride for injection, usp 3 doxorubicin. Nebivolol effect on doxorubicininduced cardiotoxicity in.
Early cardiotoxicity of doxorubicin consists mainly of sinus tachycardia andor ecg abnormalities such as. In this study we wanted to investigate if opening of mitochondrial katpchannels by diazoxide is protective against doxorubicin cardiotoxicity, and if 5hydroxydecanoate 5hd, a selective mitochondrial katpchannel. Pdf reversal of doxorubicininduced cardiotoxicity by. Reversing certain effects of cancer drug therapies may not always be possible. If you have not installed and configured the adobe acrobat reader on your system. Doxorubicin cardiotoxicity and melphalan annals of. Oxidative stress is a major cause of doxorubicininduced cardiotoxicity. 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.
Mechanism of doxorubicin cardiotoxicity evaluated by. Teaching the basics of the mechanism of doxorubicininduced. Anthracycline chemotherapy and cardiotoxicity john v mcgowan 0 robin chung 0 angshuman maulik 0 izabela piotrowska 0 j malcolm walker 0 derek m yellon 0 0 the hatter cardiovascular institute, university college london, london wc1e 6hx, uk anthracycline chemotherapy maintains a prominent role in treating many forms of cancer. Cardiotoxicity is a condition when there is damage to the heart muscle. Its use however has been affected by its cardiotoxicity. Consequently, the importance of posttreatment followups is becoming increasingly relevant to the discussion. Irreversible myocardial toxicity, manifested in its. Mechanisms and management of doxorubicin cardiotoxicity.
Cardiotoxicity was compared in 21 patients receiving doxorubicin intravenously over 48 or 96 hours and in 30 control patients treated by standard intravenous injection. Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. Cardiotoxic effects of anthracycline therapy are a major cause of morbidity for childhood cancer survivors. Diazoxide protects against doxorubicininduced cardiotoxicity. Children and adolescents are at an increased risk for developing delayed cardiotoxicity following doxorubicin administration. Potentiation of doxorubicin cardiotoxicity by iron loading in. The essential feature of reactive attachment disorder rad is a markedly. Cardiotoxicity was monitored by noninvasive methods, and endomyocardial biopsy specimens were studied by electron microscopy.
This study evaluates early evidence of cardiotoxicity in patients treated with highdose doxorubicin given as a continuous infusion. Goldman l, johnstone d, reduto l, duffy t, schwartz p, gottschalk a, zaret bl. Anthracyclines ie, doxorubicin and epirubicin, mainly used for the. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicin induced cardiac failure. Modeling doxorubicininduced cardiotoxicity in human. Doxorubicin dox, or adriamycin, an anthracycline antibiotic discovered serendipitously as a chemotherapeutic drug several decades. Patients receiving doxorubicin adriamycin assessment.
Serial radionuclide assessment of doxorubicin cardiotoxicity in cancer patients with abnormal baseline resting left ventricular performance. Cardiotoxicity associated with doxorubicin cardiotoxicity associated with doxorubicin mallinson, jane 20031101 00. Patient information for doxorubicin solution for injection 2mgml including dosage instructions and possible side effects. Patients receiving doxorubicin adriamycin potential. Pdf insights into mechanisms of doxorubicin cardiotoxicity. The mechanisms of doxorubicin induced cardiotoxicity dic remain incompletely understood. Frontiers cardiotoxicity of anticancer therapeutics. Doxorubicin dox, is a highly active anticancer agent, but its clinical use is limited by its severe cardiotoxic side. Some of the common drugs that are used to treat cardiotoxicity may include. However, the utility of dox is compromised by its potential lethal cardiotoxicity. By danubia silva dos santos and regina coeli dos santos. Doxorubicin is an effective antitumor agent with a cumulative dosedependent cardiotoxicity. Drug schedule relative myelosuppressive potency of single dose compared with doxorubicin given by standard schedule approximate relative cardiotoxicity cardiotoxicity index compared with doxorubicin given by standard schedulec recommended maximum doseb mgm2 doxorubicin rapid infusion 1 1 1 400 doxorubicin weekly 1 0.
Anthracycline chemotherapy and cardiotoxicity pdf paperity. Jci cardiotoxicity of doxorubicin is mediated through. May 27, 2014 chemotherapy with doxorubicin is limited by cardiotoxicity. The precise mechanisms underlying the cardiotoxicity of doxorubicin are not clear, but impairment of calcium homeostasis, generation of iron complexes, production of. In addition to its principal toxic mechanisms involving iron and redox reactions, recent studies have described new mechanisms of doxorubicininduced cell death, including abnormal protein processing, hyperactivated innate immune responses, inhibition of neuregulin1 nrg1erbbher. However, current research into managing and monitoring cardiotoxicity and the various side effects arising from both modern and traditional therapeutics have been very promising. The authors tested the hypothesis that toxicity to dox may be modulated by mutations that result in.
Tissue doppler imaging for anthracycline cardiotoxicity. In order to examine an effect of doxorubicin on cardiomyocytes apoptosis in nd1. Highly potent visnagin derivatives inhibit cyp1 and prevent doxorubicin cardiotoxicity. Pdf doxorubicininduced cardiotoxicity in adult indian.
This multicenter cohort study pools data from more than 28 000 children with cancer who had survived 5 or more years to evaluate the optimal dose equivalence ratio for lateonset cardiomyopathy between doxorubicin and other 3 other anthracyclines daunorubicin, epirubicin, and idarubicin and the. Doxorubicin cardiotoxicity is thought to be mediated through freeradical injury. Endomyocardial biopsy specimens and test results of cardiac function were obtained before, during, and after treatment. Yeh, mdy abstract anthracycline compounds are major culprits in chemotherapyinduced cardiotoxicity, which is the chief limiting factor in. The cardiotoxicity of doxorubicin is becoming an interdisciplinary point of interest given a growing population of cancer survivors. The biopsy specimens were examined by light and electron microscopy and were graded. The incidence of doxorubicin cardiomyopathy is primarily related to its dose.
Strategies for prevention of cardiotoxicity identifying patients with high cardiac risk modifying life style to decrease cardiac risk using less cardiotoxic regimens if possible the use of dexrazoxane in metastatic patients requiring anthracycline chemotherapy doses 300 or 540 mgm2 for doxorubicin and epirubicin, respectively. Pharmaceutical measures to prevent doxorubicininduced. It binds 67 to cell membranes as well as plasma proteins. Dexrazoxane hydrochloride may be used to prevent or reduce the occurrence and severity of heart damage cardiomyopathy caused by doxorubicin adriamycin. Derivation of anthracycline and anthraquinone equivalence. Ris zotero endnote bibtex medlars procite refworks reference manager. This may be due to chemotherapy drugs, or other medications you may be taking to control your disease. However, cumulative dose dependent cardiotoxicity has been a major hurdle where doxorubicin is the primary choice as an antitumor drug. As cancer therapeutics continues to improve and progress, the adverse side effects associated with anticancer treatments have also attracted more attention and have become extensively explored.
A population of 50 childhood cancer survivors 32 males and 18 females who have been treated with anthracyclines was evaluated. Efficacy and cardiotoxicity of liposomal doxorubicinbased. However, the role of rutin on doxorubicin induced cardiotoxicity has yet to be discovered. Cardiotoxicity is more common in patients over age 70 and under age 2, because their cardiac systems are more susceptible to. This chapter discusses the involvement of multiple cardiac cell. Adriamycin must not be given by the intramuscular or subcutaneous route. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicininduced cardiac failure. Subsequent research has led to many other anthracycline. The incidence of chronic doxorubicin cardiotoxicity is much lower, with an estimated incidence of about 1. Cardiotoxicity, doxorubicin, rnabinding protein quaking, statins.
Cardiotoxicity associated with doxorubicin, cancer nursing. Doxorubicin induced cardiotoxicity in adult indian patients on chemotherapy article pdf available in indian journal of medical and paediatric oncology 301. Eligible studies included randomized controlled trials directly comparing the efficacy and cardiotoxicity of liposomal doxorubicinbased chemotherapy with conventional doxorubicin in advanced breast cancer with adequate data. 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. Doxorubicin induces cardiotoxicity through upregulation of.
Doxorubicin and daunorubicin together can be thought of as prototype compounds for the 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. Both of these studies emphasize the critical role of iron in the pathogenesis of doxorubicininduced cardiotoxicity. Protective role of nd1 in doxorubicininduced cardiotoxicity. Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. Abstractthe clinical use of the antitumor anthracycline doxorubicin is limited by the risk of severe. Serious irreversible myocardial toxicity with delayed congestive. This article is from frontiers in pharmacology, volume 5.
Insights into mechanisms of doxorubicin cardiotoxicity. Doxorubicin showed better activity than daunorubicin against mouse tumors, and especially solid tumors. It has been hypothesized that doxorubicin dependent cardiotoxicity occurs through ros production and possibly cellular iron accumulation. The utility of anthracycline antineoplastic agents in the clinic is compromised by the risk of cardiotoxicity. It has been hypothesized that doxorubicindependent cardiotoxicity occurs through. Followup cardiac evaluations are recommended periodically to monitor for this effect. Doxorubicin cardiomyopathy fulltext cardiology 2010, vol. The aim of this retrospective evaluation is to assess the efficacy of tissue doppler imaging in the early detection of myocardial alterations in these patients. The anthracycline, doxorubicin dox, is one of the most widely used and active cytotoxic agents in cancer chemotherapy. Potentiation of doxorubicin cardiotoxicity by iron loading.
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