It also showed a higher therapeutic index, yet the cardiotoxicity remained. 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. Other agents that may induce a cardiac event include paclitaxel, etoposide, teniposide. Doxorubicin cardiotoxicity is associated with the generation of free radicals, and involves not only lipid. Doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. Children and adolescents are at an increased risk for developing delayed cardiotoxicity following doxorubicin administration. Previously, anthracyclineinduced cardiotoxicity was primarily attributed to irondependent generation of reactive oxygen species and subsequent oxidative damage. Doxorubicin can be reduced to a semiquinone not depicted by nadph oxidase or enos. Doxorubicin dox is a widely used chemotherapeutic agent with known cardiotoxic properties, while calorie restriction cr and exercise have welldocumented cardioprotective effects.
Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of streptomyces peucetius var. The manifestations are usually chest pain due to myopericarditis andor palpitations due to sinus tachycardia, paroxysmal nonsustained supraventricular tachycardia and. Jci insight highly potent visnagin derivatives inhibit. Doxorubicin is given by injection into a vein common side effects include hair loss, bone marrow suppression. Unfortunately, it causes cumulative and dosedependent cardiotoxic side effects. However, the dosedependent cardiotoxic effects of doxorubicin can limit patient. Doxorubicin is effective in controlling a wide variety of canine and feline tumors table 15. Insights into mechanisms of doxorubicin cardiotoxicity. Anthracyclines such as doxorubicin are highly effective chemotherapy agents used to treat many common malignancies. Download fulltext pdf anthracycline chemotherapy and cardiotoxicity article pdf available in cardiovascular drugs and therapy 311 february 2017 with 376 reads. Risk factors that predispose patients to cardiomyopathy include advanced age, previous radiotherapy to the mediastinum, and concurrent cyclophosphamide therapy 2. This cardiotoxicity often limits chemotherapy for malignancies and is associated with poor prognosis.
Mar 16, 2017 doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. Defining cardiotoxicity of doxorubicin and trastuzumab. Anthracycline chemotherapy maintains a prominent role in treating many forms of cancer. It is often used together with other chemotherapy agents. Pdf repeated remote ischemic conditioning protects. The incidence of acute cardiotoxicity is approximately 11% 3, 4. Modeling doxorubicininduced cardiotoxicity in human. Proposed mechanisms of doxorubicin doxinduced cardiotoxicity. Doxorubicin, sold under the brand name adriamycin among others, is a chemotherapy medication used to treat cancer. Aug 01, 2019 anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. The mechanisms of doxorubicininduced cardiotoxicity. Cardiotoxic side effects limit their dosing and improved cancer outcomes expose the cancer survivor to increased cardiovascular morbidity and mortality. Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines.
Doxorubicin showed better activity than daunorubicin against mouse tumors, and especially solid tumors. Transcriptomic profiling reveals p53 as a key regulator of. Polyphenols, autophagy and doxorubicininduced cardiotoxicity. We previously identified visnagin as protecting against doxorubicin toxicity in cardiac but not tumor cells. 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. Followup cardiac evaluations are recommended periodically to monitor for this effect. Both groups were studied prospectively and were well matched by risk factors for doxorubicin cardiotoxicity.
Doxorubicin can cause fetal harm when administered to a pregnant woman. Cardiotoxicity of chemotherapeutic agents springerlink. Jul 23, 2015 liposomal doxorubicin based chemotherapy was associated with a significant reduction in the risk of cardiotoxicity or 0. Alkylating agents such as cyclophosphamide, ifosfamide, cisplatin, carmustine, busulfan, chlormethine and mitomycin have also been associated with cardiotoxicity. Cardiotoxicity from drug developmental perspective. Dox undergoes redox cycling which results in enhanced production of reactive oxygen species ros, mitochondrial depolarization and subsequent apoptosis 2.
Scherrercrosbie, in anticancer treatments and cardiotoxicity, 2017. The mechanisms of doxorubicin induced cardiotoxicity remain incompletely understood. Subsequent research has led to many other anthracycline. Resveratrol attenuates doxorubicin induced cardiotoxicity in rats by upregulation of vascular endothelial growth factor b. Genetic determinants contributing to this variation are difficult to study using current mouse models. Lymphoma is especially sensitive to doxorubicin and the prognosis improves if the multiagent protocol includes doxorubicin. It is routinely used in the clinic as a chemotherapeutic agent for the treatment for various cancers including both solid and hematological malignancies. Jun 12, 2019 doxorubicin is an important anticancer drug in the clinic. Efficacy and cardiotoxicity of liposomal doxorubicinbased. The cardiotoxicity of doxorubicin is becoming an interdisciplinary point of interest given a growing population of cancer survivors. Pdf doxorubicininduced cardiotoxicity researchgate.
Anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. Cardiotoxicity is defined as toxicity that affects the heart by the us national cancer institute 1. Doxorubicininduced heart failure can appear very late after the last 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. 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 cardiotoxicity index compared with doxorubicin given by standard schedulec recommended maximum doseb mgm2 doxorubicin rapid infusion 1 1 1 400 doxorubicin weekly 1 0. Dec 11, 2009 doxorubicin cardiotoxicity can be acute, occurring during and within 23 days of its administration. Doxorubicin cardiotoxicity can be acute, occurring during and within 23 days of its administration. The overall incidence of cardiotoxicity in adults receiving standard doses of doxorubicin is relatively low 199.
Another influential factor in chemotherapyinduced cardiotoxicity is the peak serum concentration reached during administration. It is a potent anthracycline antibiotic first discovered from the actinobacteria streptomyces peucetius in the 1960s. A patient is reported who developed progressive cardiomyopathy two and onehalf years after receiving 580 mgm2 which apparently represents late, late cardiotoxicity. 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. The cause of doxinduced cardiotoxicity is multifactorial and includes free radicalinduced. Doxorubicininduced cardiotoxicity in collaborative cross cc. However, in a large metaanalysis by van dalen et al. Doxorubicin hydrochloride is an orangered, crystalline, hygroscopic powder that is soluble in water and slightly soluble in methanol. Doxorubicin on a weekly schedule 2 or prolonged infusions 3 allow exceeding these limits to a variable degree. Effects of calorie restriction and voluntary exercise on. Mar 15, 2019 previously, anthracyclineinduced cardiotoxicity was primarily attributed to irondependent generation of reactive oxygen species and subsequent oxidative damage.
Highly potent visnagin derivatives inhibit cyp1 and. Liposomal doxorubicin based chemotherapy was associated with a significant reduction in the risk of cardiotoxicity or 0. However, the molecular mechanism underlying this cardiotoxicity is yet to be fully elucidated. The mechanisms of doxorubicin induced cardiotoxicity dic remain incompletely understood. The manifestations are usually chest pain due to myopericarditis andor palpitations due to sinus tachycardia, paroxysmal nonsustained supraventricular tachycardia and premature atrial and ventricular. Attenuation of doxorubicininduced cardiotoxicity in a human in vitro. Teaching the basics of the mechanism of doxorubicin. Doxorubicininduced cardiotoxicity in collaborative cross. The incidence of acute cardiotoxicity is approximately 11% 3,4.
Doxorubicin is a highly efficacious anticancer drug but causes cardiotoxicity in many patients. Wed like to understand how you use our websites in order to improve them. The complex and not completely understood pathogenesis of this complication makes difficult to design successful preventive or curative measures. Rats were divided into 4 groups based on their food intake ad libitum. Find, read and cite all the research you need on researchgate. 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. Drug schedule relative university of wisconsinmadison. First published january 2, 2014 citation information. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation yoshihiko ichikawa, tejaswitha jairaj naik, hossein ardehali published february 3, 2014. Deficits of mitochondrial function, biogenesis, and energy metabolism have recently emerged as key contributors to heart failure.
Doxorubicin cardiotoxicity and melphalan annals of internal. In a network metaanalysis, the ranking order of cardiotoxicity was doxorubicin worst, epirubicin, dd, ld, and ed best. A largescale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an. Doxorubicin dox, a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicin induced cardiomyopathy dic. Early detection of anthracycline cardiotoxicity and. Cytostatic antibiotics of the anthracycline class are the best known of the chemotherapeutic agents that cause cardiotoxicity. 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. The exact pathogenesis of doxinduced cardiotoxicity remains to be fully elucidated. Oct 19, 2012 cytostatic antibiotics of the anthracycline class are the best known of the chemotherapeutic agents that cause cardiotoxicity. Endomyocardial biopsy specimens and test results of cardiac function were obtained before, during, and after treatment. Anthracycline therapy is associated with an increase in the risk for developing heart failure with significant associated morbidity and mortality 1. Doxorubicin, whose doselimiting toxicity is cardiomyopathy, was given to four cancer patients. Jci insight highly potent visnagin derivatives inhibit cyp1.
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. Severe cardiotoxicity limits the use of doxorubicin in cancer treatment. Request pdf on may 20, 2019, abir khan and others published defining cardiotoxicity of doxorubicin and trastuzumab. This includes breast cancer, bladder cancer, kaposis sarcoma, lymphoma, and acute lymphocytic leukemia. 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 and daunorubicin can cause dosedependent cardiomyopathy in children and adults 1, 2. Primarily, cardiotoxic drugs may induce cardiovascular adverse effects in a. Doxorubicin induces cardiotoxicity through upregulation of. Pdf insights into mechanisms of doxorubicin cardiotoxicity. Doxorubicin is an important anticancer drug in the clinic. The basic mechanisms of cardiotoxicity may involve direct pathways for reactive oxygen species generation and topoisomerase 2 as well as other indirect. Jci cardiotoxicity of doxorubicin is mediated through. 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.
Mechanisms of cardioprotective effect of aged garlic. Reduction of doxorubicin cardiotoxicity by prolonged. The anthracyclines and related compounds doxorubicin, daunorubicin, idarubicin, epirubicin, and the anthraquinone mitoxantrone are among the chemotherapeutic agents implicated in cardiotoxicity. 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. 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. 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. 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. Doxorubicin was teratogenic and embryotoxic at doses of 0. Doxorubicin toxicity involves the generation of reactive oxygen species ros and hence several antioxidants and plant products have been tried to minimise the cardiotoxicity. Dox is a quinonecontaining anthracycline family of drugs. Doxorubicin is a dna interchelator that inhibits topoisomerase ii thereby inhibiting cancer cell growth. Chen, 1,3 anita vohra, 2 an chi, 4 ivan cornellataracido, 4 huijun wang, 4 douglas g. Jci insight mitochondriadependent ferroptosis plays a.
The biopsy specimens were examined by light and electron microscopy and were graded. Oxidative stress is a major cause of doxorubicininduced cardiotoxicity. 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. So the present study was designed to investigate how age could. As the population of cancer survivors who have been. Both of these studies emphasize the critical role of iron in the pathogenesis of doxorubicininduced cardiotoxicity. Aug 05, 2014 another influential factor in chemotherapyinduced cardiotoxicity is the peak serum concentration reached during administration. Although cardiomyocyte has been considered a classical cellular target, other cells including various types of. Doxorubicin is a cell cyclenonspecific drug but is most active in the s phase.
Sexual dimorphism of doxorubicinmediated cardiotoxicity. The cause of doxinduced cardiotoxicity is multifactorial and. 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. Other agents that may induce a cardiac event include paclitaxel, etoposide, teniposide, the vinca. Cardiotoxicity is a wellrecognized side effect of anthracycline therapy that limits the total amount of drug administered and can cause heart failure. Congestive heart failure in patients treated with doxorubicin. 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. Doxorubicin induces cardiotoxicity through upregulation of death. Teaching the basics of the mechanism of doxorubicininduced.
Anthracycline chemotherapy and cardiotoxicity springerlink. Pdf repeated remote ischemic conditioning protects against. 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. 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 authors declare that they have no conflict of interest. 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. Nebivolol effect on doxorubicininduced cardiotoxicity in. Molecular mechanisms of doxorubicininduced cardiotoxicity.
426 540 193 564 31 646 770 463 386 413 1435 504 1300 524 1483 833 9 1103 853 1078 131 1318 629 313 837 438 1281 656 26 189 210 565 75 671 507 1268 475 663 1061 363 1032 1135