Cardioprotective effects of carvedilol in inhibiting doxorubicininduced cardiotoxicity. Diohf suppresses and reverses the doxinduced cardiotoxicity by inhibiting ros release, stabilizing mitochondrial function and. Related cardiomyopathy perhaps the most predictive measure of the development of anthracyclinerelated cardiotoxicity is the total cumulative dose. The complex and not completely understood pathogenesis of this complication makes difficult to design successful preventive or curative measures. Among the most cardiotoxic agents are anthracyclines, such as doxorubicin, epirubicin and daunorubicin, that. It is widely utilized in the therapy of variety of haematological and solid tumours, although its. Doxorubicin hydrochloride for injection, usp patient. Principal investigator r01hl146443 512019 4302024 nih.
From mechanisms to development of efficient therapy. A pairwise comparative metabolomics approach was used to delineate the potential metabolic processes in the present study. It is usually evident within 30 days of administration of its last dose, but it may occur even after 610 years after its administration. Objectives the purpose of this study was to identify early doxorubicin induced cardiotoxicity by serial multiparametric cardiac magnetic resonance cmr and its pathological correlates in a large animal model. Propolis doxorubicin cardiotoxicity antioxidant pdf. Doxorubicin induced cardiomyopathy genetic and rare. Doxorubicininduced cardiotoxicity in collaborative cross cc. Carbonyl reductase cbr has been implicated in the development of doxorubicininduced cardiotoxicity. However, cumulative dose dependent cardiotoxicity has been a major hurdle where doxorubicin is the primary choice as an antitumor drug.
Background anthracyclineinduced cardiotoxicity is a major clinical problem, and early cardiotoxicity markers are needed. The mechanisms of doxorubicin induced cardiotoxicity remain incompletely understood. Anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. Yeh, mdy abstract anthracycline compounds are major culprits in chemotherapyinduced cardiotoxicity, which is the chief limiting factor in. Siog apac 2014 12 th to th july breast cancer in older adults cardiac toxicity in breast cancer.
Quaking inhibits doxorubicinmediated cardiotoxicity through. Cardioprotection of dexrazoxane dzr against doxorubicin doxinduced cardiotoxicity is contentious and the indicator is controversial. Cardiotoxicity is a limiting factor in the treatment of cancer with adriamycin. Genomic prediction of chemotherapyinduced cardiotoxicity. Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of streptomyces peucetius var. Attenuation of doxorubicininduced cardiotoxicity in a human in vitro cardiac model. This study evaluates early evidence of cardiotoxicity in patients treated with highdose doxorubicin given as a continuous infusion. The iron chelator icrf187 has been shown to protect against dox induced cardiotoxicity. Mechanism of doxorubicin cardiotoxicity evaluated by. Original article alleviation of doxorubicininduced. Nabati m, janbabai g, baghyari s, esmaili m, yazdani j.
Doxorubicin induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both. Data was collected on patients who received 90 mgm 2 doxorubicin as a continuous infusion and 10 gm. Doxorubicin is a highly effective antineoplastic agent, but it can produce the serious side effects of acute cardiac injury and chronic congestive heart failure. Doxorubicininduced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both. Adriamycin induced cardiotoxicity mostly develops during the course of therapy up to two months from its termination but late events several months to years after treatment termination have occurred. Prevention of anthracycline induced cardiotoxicity challenges and opportunities pimprapa vejpongsa, md, edward t.
This may suggest that endogenous reproductive hormones can in part suppress doxinduced. Ninetysix balbc mice were randomly divided into two supergroups. Oxidative stress is a major cause of doxorubicin induced cardiotoxicity. The mechanisms of doxorubicininduced cardiotoxicity. Serial magnetic resonance imaging to identify early stages. Several recent studies have leveraged hpsccms to develop a mechanistic understanding of doxorubicin induced cardiotoxicity burridge et al. Uses are limited by dosedependent cardiotoxicity and hepatotoxicity. Dec 11, 2009 the incidence of chronic doxorubicin cardiotoxicity is much lower, with an estimated incidence of about 1. Importantly, genetic mutation of cyp1a protected zebrafish against doxorubicin.
The pathogenesis of doxorubicin induced cardiotoxicity is complex and multifactorial. Anthracycline antibiotic doxorubicin dox is a very potent and extensively prescribed chemotherapeutic drug. Prevention of anthracyclineinduced cardiotoxicity challenges and opportunities pimprapa vejpongsa, md, edward t. Doxorubicin, sold under the brand name adriamycin among others, is a chemotherapy medication used to treat cancer. Alleviation of doxorubicininduced cardiotoxicity by hong huang.
Methods the authors declare that all supporting data are availa ble within the article and its online supplementary files. Yeh, mdy abstract anthracycline compounds are major culprits in chemotherapy induced cardiotoxicity, which is the chief limiting factor in delivering optimal chemotherapy to cancer patients. Development of an effective drug to prevent and treat cardiac toxicity induced by dox. The mechanisms of doxorubicin induced cardiotoxicity dic remain incompletely understood. Doxorubicininduced cardiotoxicity in collaborative cross. To determine antioxidant activity of biological samples, and the. Doxorubicin is given by injection into a vein common side effects include hair loss, bone marrow suppression. The present study investigated whether the practice of exercise has a protective effect against cardiac toxicity induced by doxorubicin dox. Jci cardiotoxicity of doxorubicin is mediated through. The incidence of acute cardiotoxicity is approximately 11% 3,4. This includes breast cancer, bladder cancer, kaposis sarcoma, lymphoma, and acute lymphocytic leukemia. An overview of all apoptotic pathways involved in doxorubicininduced cardiotoxicity is given in fig. Finally, hearts from patients with doxorubicininduced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal.
For language access assistance, contact the ncats public information officer. Doxorubicin, nanoparticles, liposomal, polymeric, protein, gold, cardiotoxicity, nanocarriers. Pdf on nov 14, 2018, danubia silva dos santos and others published doxorubicininduced cardiotoxicity. Finally, hearts from patients with doxorubicin induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal. Objectives the purpose of this study was to identify early doxorubicininduced cardiotoxicity by serial multiparametric cardiac magnetic resonance cmr and its pathological correlates in a large animal model. Doxorubicin dox is the predominant anthracycline, but its use is limited due to cardiotoxicity octavia et al.
Doxorubicin cardiotoxicity and the protective effects of exercise total direct costs. In humans, dox cardiotoxicity manifests over two time scales. Postmenopausal and hypertensive females are two highrisk groups for developing adverse effects following dox treatment. Together, these results provide strong evidence that cyp1 is an important contributor to doxorubicin. Although multiple mechanisms are involved in doxorubicininduced cardiotoxicity, generation of ros which causes lipid peroxidation and depletion of antioxidant enzymes is considered as the major. Reduction of doxorubicininduced cardiotoxicity using. The cardiotoxicity of doxorubicin is becoming an interdisciplinary point of interest given a growing population of cancer survivors. Animal studies have shown activity in a spectrum of experimental tumors, immunosuppression, carcinogenic properties in rodents. This study investigat ed whether hong huang decoction hhd inhibits dox induced cardiotoxicity. Anthracycline therapy is associated with an increase in the risk for developing heart failure with significant associated morbidity and mortality 1. It has also become apparent that doxorubicin can induce apoptosis via.
Aug 01, 2019 anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. This study investigat ed whether hong huang decoction hhd inhibits doxinduced cardiotoxicity. Mechanistically, qki inhibits doxorubicinmediated cardiotoxicity via regulating cardiac circular rnas. Simvastatin was administrated daily one week before doxorubicin treatment. Review of trastuzumabinduced cardiotoxicity in elderly treatment of chemotherapyinduced cardiotoxicity 3. If you have problems viewing pdf files, download the latest version of adobe reader. Serial magnetic resonance imaging to identify early stages of. Modeling trastuzumabrelated cardiotoxicity in vitro using. Several recent studies have leveraged hpsccms to develop a mechanistic understanding of doxorubicininduced cardiotoxicity burridge et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. Doxorubicin is a highly efficacious anticancer drug but causes cardiotoxicity in many patients. Doxorubicin doxinduced cardiotoxicity limits the use of dox as an antitumor drug. Doxorubicin induced heart failure can appear very late after the last administration.
The anthracyclines and related compounds doxorubicin, daunorubicin, idarubicin, epirubicin, and the anthraquinone mitoxantrone are among the chemotherapeutic agents implicated in cardiotoxicity. Diohf protects against doxorubicininduced cardiotoxicity through. This study investigated the potential cardioprotective effects of rsvl against dox induced cardiotoxicity. Doxorubicin dox induced cardiotoxicity limits the use of dox as an antitumor drug. Genetic and rare diseases information center gard po box 8126, gaithersburg, md 208988126 tollfree. Doxorubicin consists of a naphthacenequinone nucleus linked through a glycosidic bond at ring atom 7 to an amino sugar, daunosamine.
Protection from doxorubicininduced cardiac toxicity in. Dox exposure to endothelial cells and cardiomyocytes caused apoptotic cell death at submicromolar. Although cardiomyocyte has been considered a classical cellular target, other cells including various types of. A largescale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an estimated 7% of patients developed doxorubicin. Dexrazoxane, a drug that attenuates doxorubicin induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin induced cardiac damage. We then update the findings of molecular biology of doxinduced cardiomyopathy including molecular mechanisms, established and putative. Teaching the basics of the mechanism of doxorubicininduced. At present, adriamycininduced chf can best be prevented by limiting the total dose. Doxorubicin induced cardiomyopathy typically results in dilated cardiomyopathy, with all four cardiac chambers being enlarged. The incidence of doxorubicin cardiomyopathy is primarily related to its dose. A largescale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an. Protective effects of dexrazoxane against doxorubicin. Modeling doxorubicininduced cardiotoxicity in human.
Finally, hearts from patients with doxorubicin induced. Department of physiology, faculty of medicine, masaryk university, kamenice 5, cz625 00 brno. Get a printable copy pdf file of the complete article 883k, or click on a. In support of this model, an inhibition of mrp2 expression by a bacterial toxin decreased biliary clearance of doxorubicin and increased its plasma concentration. 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. R01 doxorubicininduced respiratory dysfunction and the protective effects of exercise total direct. Topoisomerase iibeta mediated dna doublestrand breaks. We observed that cardiac enzymes such as ldh and ck were signifi. Reduction of doxorubicininduced cardiotoxicity using nanocarriers. Background anthracycline induced cardiotoxicity is a major clinical problem, and early cardiotoxicity markers are needed.
New signal transduction paradigms in anthracyclineinduced. Early evidence of cardiotoxicity and tumor response in. The lifethreatening toxic side effects are related to cardiotoxicity heart failure, cardiomyopathy that occurs many years after the cessation of. Congestive heart failure in patients treated with doxorubicin. Effect of desferrioxamine on doxorubicininduced cardiotoxicity and haematotoxicity in mice. Pdf doxorubicininduced cardiotoxicity in adult indian. However, its clinical success is limited because it increases hematotoxicity in cancer patients 14,15. Dexrazoxane, a drug that attenuates doxorubicininduced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicininduced cardiac damage. Propolis doxorubicin cardiotoxicity antioxidant pdf keywords. Acute effects occur within 48 h of infusion and are generally reversible and clinically manageable takemura and fujiwara, 2007. Doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. Quaking inhibits doxorubicinmediated cardiotoxicity. Original article simvastatin protects cardiomyocytes from. Mar 16, 2017 doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients.
Doxorubicin, also known as adriamycin or rubex, is an anthracycline antibiotic that was discovered from a mutated strain of streptomyces peucetius. Doxorubicininduced cardiotoxicity is suppressed by. Doxorubicin enhances oxysterol levels resulting in a lxr. Finally, hearts from patients with doxorubicininduced. Doxorubicin cardiotoxicity can be acute, occurring during and within 23 days of its administration. Despite being one of the most potent chemotherapeutics, doxorubicin dox facilitates cardiac toxicity by irreversibly damaging the cardiac muscle as well as severely dysregulating the immune system and impairing the resolution of cardiac inflammation. Temperatureresponsive polymersomes of poly3methyln. Carbonyl reductase cbr has been implicated in the development of doxorubicin induced cardiotoxicity. It is generally accepted that the oxidative stress evoked by doxorubicin activates apoptotic signaling leading to cardiomyocyte apoptosis, and that both the extrinsic and intrinsic apoptoticpathways are involved.
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. Despite the dosedependent response rate of sarcomas to doxorubicin, clinicians limit its cumulative dose due to cardiotoxicity. Nadph oxidase and multidrug resistance protein genetic. Doxorubicininduced cardiotoxicity is mediated by top2.
Dose reduction protocols have been proposed to avoid the risk of delayed cardiotoxicity, but this might be at the expense of the anticancer effect. Herein, we report synthesis and aqueous selfassembly of nanosized polymersomes from temperatureresponsive poly3methylnvinylcaprolactam. Role of micrornas in doxorubicininduced cardiotoxicity. Doxorubicin, heart, liver, lipid peroxidation, propolis extract, vinblastin. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicininduced cardiac failure 1, 2. Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction lvef andor signs and symptoms of. Doxorubicininduced cardiotoxicity in adult indian patients on chemotherapy article pdf available in indian journal of medical and paediatric oncology 301. Doxorubicin dox, an anthracycline therapeutic, is widely used to treat a variety of cancer types and known to induce cardiomyopathy in a time and dosedependent manner. Protection from doxorubicininduced cardiac toxicity in mice. This results in both systolic and diastolic dysfunction. 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.
The manifestations are usually chest pain due to myopericarditis andor palpitations due to sinus tachycardia, paroxysmal nonsustained supraventricular tachycardia and premature atrial and ventricular. Cardiotoxicity of doxorubicin treatment and physical activity. Attenuation of doxorubicininduced cardiotoxicity in a human in vitro. Michaela fojtu, jaromir gumulec, tibor stracina, martina raudenska, anna skotakova, marketa vaculovicova, vojtech adam, petr babula, marie novakova and michal masarik affiliation. By danubia silva dos santos and regina coeli dos santos. Doxorubicin induces cardiotoxicity through upregulation of.
It is becoming increasingly clear that apoptosis of myocardial cells plays a critical role in the onset of cardiomyopathy. Genetic determinants contributing to this variation are difficult to study using current mouse models. Molecular mechanism and protection by conventional drugs and natural products. It is often used together with other chemotherapy agents. Cardioprotective effects of carvedilol in inhibiting doxorubicin induced cardiotoxicity.
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