Both groups were studied prospectively and were well matched by risk factors for doxorubicin cardiotoxicity. Subsequent research has led to many other anthracycline. Druginduced mitochondrial dysfunction and cardiotoxicity. So the present study was designed to investigate how age could. Wed like to understand how you use our websites in order to improve them.
Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. Doxorubicininduced heart failure can appear very late after the last administration. Doxorubicin is effective in controlling a wide variety of canine and feline tumors table 15. Dec 11, 2009 doxorubicin cardiotoxicity can be acute, occurring during and within 23 days of its administration. Cardiotoxicity is defined as toxicity that affects the heart by the us national cancer institute 1. Early detection of anthracycline cardiotoxicity and. Cardiac toxicity is a major complication which limits the use of adriamycin as a chemotherapeutic agent cardiomyopathy is frequent when the total dose exceeds 600 mgm2 and occurs within one to six months after cessation of therapy. Highly potent visnagin derivatives inhibit cyp1 and. The manifestations are usually chest pain due to myopericarditis andor palpitations due to sinus tachycardia, paroxysmal nonsustained supraventricular tachycardia and. Doxorubicininduced cardiotoxicity in collaborative cross cc. Mechanisms of cardioprotective effect of aged garlic. Pdf repeated remote ischemic conditioning protects.
Pdf doxorubicininduced cardiotoxicity researchgate. However, the molecular mechanism underlying this cardiotoxicity is yet to be fully elucidated. Rats were divided into 4 groups based on their food intake ad libitum. However, in a large metaanalysis by van dalen et al. Primarily, cardiotoxic drugs may induce cardiovascular adverse effects in a. Congestive heart failure in patients treated with doxorubicin. Cytostatic antibiotics of the anthracycline class are the best known of the chemotherapeutic agents that cause cardiotoxicity. Another influential factor in chemotherapyinduced cardiotoxicity is the peak serum concentration reached during administration.
This includes breast cancer, bladder cancer, kaposis sarcoma, lymphoma, and acute lymphocytic leukemia. Jun 12, 2019 doxorubicin is an important anticancer drug in the clinic. Previously, anthracyclineinduced cardiotoxicity was primarily attributed to irondependent generation of reactive oxygen species and subsequent oxidative damage. Teaching the basics of the mechanism of doxorubicin. Transcriptomic profiling reveals p53 as a key regulator of. In this study, we sought to develop more potent visnagin analogs in order to use these analogs as tools to clarify the mechanisms of visnaginmediated cardioprotection. Cardioprotectors 4 and liposomal preparations with the potential for reduced toxicity relative to free doxorubicin 57, represent another potential solution to the problem of cardiotoxicity. Doxorubicin showed better activity than daunorubicin against mouse tumors, and especially solid tumors. Cardiotoxicity of chemotherapeutic agents springerlink. Doxorubicin induces cardiotoxicity through upregulation of. Pristimerin protects against doxorubicininduced cardiotoxicity and fibrosis through modulation of nrf2 and mapknfkappab signaling pathways dina s elagamy,1,2 khaled m elharbi,3 saad khoshhal,3 nishat ahmed,1 mohamed a elkablawy,4,5 ahmed a shaaban,2,6 hany m abohaded3,7 1department of pharmacology and toxicology, college of pharmacy, taibah university, almadinah almunawwarah. Liposomal doxorubicinbased chemotherapy was associated with a significant reduction in the risk of cardiotoxicity or 0. Age has been proven to have cardioprotective effect against doxinduced cardiotoxicity.
Mar 15, 2019 previously, anthracyclineinduced cardiotoxicity was primarily attributed to irondependent generation of reactive oxygen species and subsequent oxidative damage. A patient is reported who developed progressive cardiomyopathy two and onehalf years after receiving 580 mgm2 which apparently represents late, late cardiotoxicity. The mechanisms of doxorubicininduced cardiotoxicity. Anthracycline therapy is associated with an increase in the risk for developing heart failure with significant associated morbidity and mortality 1. Anthracyclines are among the most widely used chemotherapeutic agents and have been shown to be effective in a wide range of tumors, in particular, breast cancer and lymphoma. No studies have investigated the effects of cr alone or the combined effects of cr and exercise on dox cardiotoxicity. The mechanisms of doxorubicininduced cardiotoxicity remain incompletely understood. Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of streptomyces peucetius var. It is a potent anthracycline antibiotic first discovered from the actinobacteria streptomyces peucetius in the 1960s.
It is routinely used in the clinic as a chemotherapeutic agent for the treatment for various cancers including both solid and hematological malignancies. Request pdf on may 20, 2019, abir khan and others published defining cardiotoxicity of doxorubicin and trastuzumab. The mechanisms of doxorubicin induced cardiotoxicity dic remain incompletely understood. Cancer management and research nebivolol effect on doxorubicininduced cardiotoxicity in breast cancer flavia cochera 0 daniel dinca 0 0 cardiology department, victor babes university of medicine and pharmacy, timisoara, romania 8 1 0 2 l u j 7 1 n o 7 0 2. Defining cardiotoxicity of doxorubicin and trastuzumab. Molecular mechanisms of doxorubicininduced cardiotoxicity. Download fulltext pdf anthracycline chemotherapy and cardiotoxicity article pdf available in cardiovascular drugs and therapy 311 february 2017 with 376 reads. It also showed a higher therapeutic index, yet the cardiotoxicity remained. In a network metaanalysis, the ranking order of cardiotoxicity was doxorubicin worst, epirubicin, dd, ld, and ed best. The median cumulative dose for those receiving continuous infusion was 600 mgm 2 body surface area range, 360 to 1500 mgm 2 compared with 465 mgm 2 range, 290 to 680 mgm 2 in the control group p 0. Doxorubicin is a highly efficacious anticancer drug but causes cardiotoxicity in many patients.
Pdf insights into mechanisms of doxorubicin cardiotoxicity. Doxorubicin hydrochloride is an orangered, crystalline, hygroscopic powder that is soluble in water and slightly soluble in methanol. Risk factors that predispose patients to cardiomyopathy include advanced age, previous radiotherapy to the mediastinum, and concurrent cyclophosphamide therapy 2. The anticancer drug doxorubicin dox also referred to as adriamycin is highly effective in the treatment of a broad range of cancers. The mechanisms of doxorubicin induced cardiotoxicity remain incompletely understood. Doxorubicin is an important anticancer drug in the clinic. Although cardiomyocyte has been considered a classical cellular target, other cells including various types of. Anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient.
Doxorubicin is a dna interchelator that inhibits topoisomerase ii thereby inhibiting cancer cell growth. The complex and not completely understood pathogenesis of this complication makes difficult to design successful preventive or curative measures. Dec 31, 2019 studies have suggested that concomitant administration of doxorubicin and calcium channel entry blockers or cardiotoxic drugs, especially those with long halflives, e. Jci insight highly potent visnagin derivatives inhibit cyp1.
Doxorubicin dox, a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicin induced cardiomyopathy dic. Children and adolescents are at an increased risk for developing delayed cardiotoxicity following doxorubicin administration. Moreover, these studies support the idea that cyp1 is an important contributor to doxorubicin cardiotoxicity and suggest that modulation of this pathway could be beneficial in the clinical setting. Jci cardiotoxicity of doxorubicin is mediated through. Liposomal doxorubicin based chemotherapy was associated with a significant reduction in the risk of cardiotoxicity or 0. Find, read and cite all the research you need on researchgate. Aug 01, 2019 anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. Doxorubicin and daunorubicin can cause dosedependent cardiomyopathy in children and adults 1, 2. Reduction of doxorubicin cardiotoxicity by prolonged. Attenuation of doxorubicininduced cardiotoxicity in a human in vitro. Mar 16, 2017 doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. Effects of calorie restriction and voluntary exercise on. In the current study using p53 mouse models, lowdose doxorubicin as administered in the clinics surprisingly revealed that the absence of p53 increases susceptibility to doxorubicin cardiotoxicity while a mutant of.
Drug schedule relative university of wisconsinmadison. Doxorubicininduced cardiotoxicity in collaborative cross. Doxorubicin, whose doselimiting toxicity is cardiomyopathy, was given to four cancer patients. Dox is a quinonecontaining anthracycline family of drugs. Severe cardiotoxicity limits the use of doxorubicin in cancer treatment. Doxorubicin toxicity involves the generation of reactive oxygen species ros and hence several antioxidants and plant products have been tried to minimise the cardiotoxicity. Doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. Oct 19, 2012 cytostatic antibiotics of the anthracycline class are the best known of the chemotherapeutic agents that cause cardiotoxicity. Pdf repeated remote ischemic conditioning protects against. The anthracyclines and related compounds doxorubicin, daunorubicin, idarubicin, epirubicin, and the anthraquinone mitoxantrone are among the chemotherapeutic agents implicated in cardiotoxicity. Doxorubicin can cause fetal harm when administered to a pregnant woman. Genetic determinants contributing to this variation are difficult to study using current mouse models. At multivariable analysis, endchemotherapy lvef hazard ratio, 1.
Modeling doxorubicininduced cardiotoxicity in human. However, the dosedependent cardiotoxic effects of doxorubicin can limit patient. Alkylating agents such as cyclophosphamide, ifosfamide, cisplatin, carmustine, busulfan, chlormethine and mitomycin have also been associated with cardiotoxicity. 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. The cause of doxinduced cardiotoxicity is multifactorial and. Highly potent visnagin derivatives inhibit cyp1 and prevent doxorubicin cardiotoxicity aarti asnani, 1,2 baohui zheng, 1 yan liu, 1 you wang, 1 howard h. The cardiotoxicity of doxorubicin is becoming an interdisciplinary point of interest given a growing population of cancer survivors.
Other agents that may induce a cardiac event include paclitaxel, etoposide, teniposide, the vinca. A largescale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an. Resveratrol attenuates doxorubicin induced cardiotoxicity in rats by upregulation of vascular endothelial growth factor b. The incidence of clinical heart failure during doxorubicin treatment in three studies comprising 630 patients with breast and lung cancer rose exponentially from 5% with a cumulative dose of 400 mgm 2 to 48% with 700 mgm 2. Oxidative stress is a major cause of doxorubicininduced cardiotoxicity. Endomyocardial biopsy specimens and test results of cardiac function were obtained before, during, and after treatment. Unfortunately, it causes cumulative and dosedependent cardiotoxic side effects. Doxorubicin dox is a widely used chemotherapeutic agent with known cardiotoxic properties, while calorie restriction cr and exercise have welldocumented cardioprotective effects.
Chen, 1,3 anita vohra, 2 an chi, 4 ivan cornellataracido, 4 huijun wang, 4 douglas g. The incidence of acute cardiotoxicity is approximately 11% 3, 4. The authors declare that they have no conflict of interest. Nebivolol effect on doxorubicininduced cardiotoxicity in. Other agents that may induce a cardiac event include paclitaxel, etoposide, teniposide. As the population of cancer survivors who have been. The basic mechanisms of cardiotoxicity may involve direct pathways for reactive oxygen species generation and topoisomerase 2 as well as other indirect. Doxorubicin, sold under the brand name adriamycin among others, is a chemotherapy medication used to treat cancer. Anthracycline chemotherapy maintains a prominent role in treating many forms of cancer.
Aug 05, 2014 another influential factor in chemotherapyinduced cardiotoxicity is the peak serum concentration reached during administration. Followup cardiac evaluations are recommended periodically to monitor for this effect. We previously identified visnagin as protecting against doxorubicin toxicity in cardiac but not tumor cells. Doxorubicin is a highly effective and widely used cytotoxic agent with application that is limited by cardiotoxicity related to the cumulative dose of the drug. Jci insight highly potent visnagin derivatives inhibit. 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. Doxorubicin was excreted in the milk of one lactating patient, with peak milk concentration at 24 hours after treatment being approxi er therapy with 70 mgm. The overall incidence of cardiotoxicity in adults receiving standard doses of doxorubicin is relatively low 199. Doxorubicin can be reduced to a semiquinone not depicted by nadph oxidase or enos. Early on, it was shown that several enzymes including the cytochrome p450 reductase, nadh dehydrogenase, and xanthine oxidoreductase could reduce dox via a oneelectron reduction mechanism,,,,, giving rise to the semiquinone intermediate that can rapidly reduce oxygen to superoxide o 2 via a futile redox.
Cardiotoxicity accounted for 45% of all drugs withdrawn between 1994 and 2006, which was due mainly to cardiac ischemiarelated and arrhythmogenic side effects. Dox undergoes redox cycling which results in enhanced production of reactive oxygen species ros, mitochondrial depolarization and subsequent apoptosis 2. With doxorubicin, the cardiotoxicity likely is dosedependent 197,204 and can develop within days after exposure to the drug 205,206 or months to years after drug treatment 193,195,207. Sexual dimorphism of doxorubicinmediated cardiotoxicity. Polyphenols, autophagy and doxorubicininduced cardiotoxicity. This cardiotoxicity often limits chemotherapy for malignancies and is associated with poor prognosis. Both of these studies emphasize the critical role of iron in the pathogenesis of doxorubicininduced cardiotoxicity. Doxorubicin on a weekly schedule 2 or prolonged infusions 3 allow exceeding these limits to a variable degree. Jul 23, 2015 liposomal doxorubicin based chemotherapy was associated with a significant reduction in the risk of cardiotoxicity or 0. Although simple to understand in theory, this definition is very broad and in the case of cancer treatments, may encompass many effects, such as cardiac dysfunction and heart failure, myocardial ischemia or.
Jci insight mitochondriadependent ferroptosis plays a. Modulation of doxorubicininduced cardiotoxicity by. Anthracycline chemotherapy and cardiotoxicity springerlink. Scherrercrosbie, in anticancer treatments and cardiotoxicity, 2017. Insights into mechanisms of doxorubicin cardiotoxicity. Cardiotoxic side effects limit their dosing and improved cancer outcomes expose the cancer survivor to increased cardiovascular morbidity and mortality. Deficits of mitochondrial function, biogenesis, and energy metabolism have recently emerged as key contributors to heart failure. Teaching the basics of the mechanism of doxorubicininduced. Proposed mechanisms of doxorubicin doxinduced cardiotoxicity.
Doxorubicin cardiotoxicity and melphalan annals of internal. The exact pathogenesis of doxinduced cardiotoxicity remains to be fully elucidated. It is often used together with other chemotherapy agents. The incidence of acute cardiotoxicity is approximately 11% 3,4. Doxorubicin cardiotoxicity can be acute, occurring during and within 23 days of its administration. Cardiotoxicity is a wellrecognized side effect of anthracycline therapy that limits the total amount of drug administered and can cause heart failure. The cause of doxinduced cardiotoxicity is multifactorial and includes free radicalinduced. Doxorubicin was teratogenic and embryotoxic at doses of 0. First published january 2, 2014 citation information. May 06, 2014 the anticancer drug doxorubicin dox also referred to as adriamycin is highly effective in the treatment of a broad range of cancers. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation yoshihiko ichikawa, tejaswitha jairaj naik, hossein ardehali published february 3, 2014. The manifestations are usually chest pain due to myopericarditis andor palpitations due to sinus tachycardia, paroxysmal nonsustained supraventricular tachycardia and premature atrial and ventricular. Anthracyclines such as doxorubicin are highly effective chemotherapy agents used to treat many common malignancies.
Lymphoma is especially sensitive to doxorubicin and the prognosis improves if the multiagent protocol includes doxorubicin. Doxorubicin is a cell cyclenonspecific drug but is most active in the s phase. Efficacy and cardiotoxicity of liposomal doxorubicinbased. 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. Doxorubicin induces cardiotoxicity through upregulation of death. Doxorubicin is given by injection into a vein common side effects include hair loss, bone marrow suppression. Doxorubicin is a dnadamaging agent that is highly effective against various types of cancers, but a subset of treated patients develop heart failure for unclear genetic reasons. Resveratrol attenuates doxorubicininduced cardiotoxicity. Cardiotoxicity from drug developmental perspective.
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