Effects of calorie restriction and voluntary exercise on. Drug schedule relative university of wisconsinmadison. The incidence of doxorubicin cardiomyopathy is primarily related to its dose. Dec 11, 2009 the incidence of chronic doxorubicin cardiotoxicity is much lower, with an estimated incidence of about 1. Doxorubicin cardiotoxicity can be acute, occurring during and within. Despite the dosedependent response rate of sarcomas to doxorubicin, clinicians limit its cumulative dose due to cardiotoxicity. Doxorubicin, whose doselimiting toxicity is cardiomyopathy, was given to four cancer patients. Aug 01, 2019 anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. 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. It also showed a higher therapeutic index, yet the cardiotoxicity remained. Anthracycline chemotherapy maintains a prominent role in treating many forms of cancer. Doxorubicin dox is a widely used chemotherapeutic agent with known cardiotoxic properties, while calorie restriction cr and exercise have welldocumented cardioprotective. The protective effects of silymarin against doxorubicin. Other agents that may induce a cardiac event include paclitaxel, etoposide, teniposide, the vinca.
Disposition of doxorubicinol doxol in patients is formation rate limited, with the terminal halflife of doxol being similar to doxorubicin. Mechanisms of anthracycline cardiotoxicity and strategies to. Doxorubicin on a weekly schedule 2 or prolonged infusions 3 allow exceeding these limits to a variable degree. 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.
Anthracycline chemotherapy and cardiotoxicity springerlink. The irondoxorubicin complex can bind dna and cell membranes producing free radicals that immediately cleave dna and cell membranes. 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. Cardiotoxicity cardiotoxicity index compared with doxorubicin given by standard schedulec recommended maximum doseb mgm2 doxorubicin rapid infusion 1 1 1 400 doxorubicin. Doxorubicin is a highly efficacious anticancer drug but causes cardiotoxicity in many patients.
The mechanisms of doxorubicininduced cardiotoxicity remain incompletely. Pdf insights into mechanisms of doxorubicin cardiotoxicity. It is available in 5 ml 10 mg, 10 ml 20 mg and 25 ml 50 mg. Oxidative stress is a major cause of doxorubicin induced cardiotoxicity. While anthracyclines are associated with increased risk of cardiomyopathy, they are also important components of many chemotherapy regimens.
Doxorubicin also has the capacity to induce free radicaloxidative damage to cells ultimately leading to cell death. The mechanisms of doxorubicininduced cardiotoxicity dic remain. The mechanisms of doxorubicin induced cardiotoxicity dic remain incompletely understood. Cardiotoxic side effects limit their dosing and improved cancer outcomes expose the. Disposition of doxorubicinol doxol in patients is formation rate limited, with.
In addition, anthracycline antitumor drugs can also generate free radicals through nonenzymatic pathways. Free radicalmediated myocyte damage was the first and most thoroughly studied mechanism proposed to explain the cardiotoxicity of ants. No studies have investigated the effects of cr alone or the combined effects of cr and exercise on dox cardiotoxicity. 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. Dox treatment is associated with adverse effects, particularly cardiac dysfunction. Doxorubicin pi may 8, 2003 3 65 sugar, producing a hydrophilic center. Cardiotoxic side effects limit their dosing and improved cancer outcomes expose the cancer survivor to increased cardiovascular morbidity and mortality. Nebivolol effect on doxorubicininduced cardiotoxicity in.
The pathogenesis of doxorubicin induced cardiotoxicity is complex and multifactorial. Endomyocardial biopsy specimens and test results of cardiac function were obtained before, during, and after treatment. In this study of the northern california oncology group, myofibrillar loss and sarcoplasmic vacuolization were identified and shown to be identical to those previously described for doxorubicin. Risk factors that predispose patients to cardiomyopathy include advanced age, previous radiotherapy to the mediastinum, and concurrent cyclophosphamide therapy 2. Doxorubicin reduction in the presence of free iron also sets up a cycle for free. The pivotal role played by mitochondrial dysfunction in doxorubicin cardiotoxicity is, furthermore, revealed by the fact that activation of mitochondrial function or biogenesis by various agents.
Doxorubicin hydrochloride for injection, usp patient. The mechanisms of doxorubicin induced cardiotoxicity remain incompletely understood. Fortytwo evaluable endomyocardial biopsies were obtained from 29 patients treated with epirubicin, the 4epimer of doxorubicin in cumulative doses ranging from 147 mgm2 to 888 mgm2. Here, we describe the incidence of doxinduced cardiotoxicity dic. There is no specific curative or preventive treatment available. Therefore, there is a clinical need for noninvasive investigation of early cardiotoxicity in oncology treatment regimens involving anthracyclines 2.
The anthracyclines and related compounds doxorubicin, daunorubicin, idarubicin, epirubicin, and the anthraquinone mitoxantrone are among the chemotherapeutic agents implicated in cardiotoxicity. Another controversy is the potential risk of increased secondary malignancy, which was reported in 1 study that added dexrazoxane to the standard. Early evidence of cardiotoxicity and tumor response in. To study the role of myocardial apoptosis following doxorubicin. Doxorubicin hydrochloride injection, usp is a sterile, isotonic, preservative free solution for intravenous use. Cytostatic antibiotics of the anthracycline class are the best known of the chemotherapeutic agents that cause cardiotoxicity. Modeling doxorubicininduced cardiotoxicity in human. Cardiomyopathy induced by doxorubicin dox is considered an extremely serious adverse effect of. Therefore, the aim of this study was to investigate.
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. Both groups were studied prospectively and were well matched by risk factors for doxorubicin cardiotoxicity. Children and adolescents are at an increased risk for. Additionally, some studies have shown that liposomal doxorubicin did not increase cardiotoxicity compared with anthracyclinefree chemotherapy 12.
The anthracycline antitumour and cardiotoxic mechanisms have not been fully. Doxorubiciniron complexes have been known since 1980, when the first studies demonstrated that doxorubicin had a strong affinity for iron, and that the iron complex could cause lipid peroxidation through its interactions with the negativelycharged membranes. The basic mechanisms of cardiotoxicity may involve direct pathways for reactive oxygen species generation and topoisomerase 2 as well as other indirect. Pdf doxorubicininduced cardiotoxicity researchgate. Doxorubicin induces cardiotoxicity through upregulation of. Jul 23, 2015 liposomal doxorubicin based chemotherapy was associated with a significant reduction in the risk of cardiotoxicity or 0. Doxorubicin dox is a cytotoxic anthracycline antibiotic and one of the important chemotherapeutic agents for different types of cancers.
Although maximally cytotoxic in s phase, doxorubicin is not cell cyclespecific. Cancer management and research nebivolol effect on doxorubicininduced cardiotoxicity in breast cancer flavia cochera 0 daniel dinca 0 0 cardiology department, victor babes. Congestive heart failure in patients treated with doxorubicin. Early detection of anthracycline cardiotoxicity and. The 6maleimidocaproyl hydrazone derivative of doxorubicin doxoemch is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage dirk lebrecht1, andrea geist 2, uwepeter ketelsen3,jorg haberstroh, bernhard setzer1, felix kratz4 and ulrich a. As discussed below, this later characteristic of free radical formation is likely the major mechanism responsible for one of the potential side effects of doxorubicincardiotoxicity.
Endomyocardial biopsy specimens and test results of cardiac function were. Therefore, egcg combined with dox could be useful to scavenge intracellular oxygen free radicals and prevent dox induced cardiotoxicity 2628. At present, doxorubicin cardiotoxicity routinely is. Anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. Mar 16, 2017 doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. The manifestations are usually chest pain due to myopericarditis andor palpitations due to sinus tachycardia, paroxysmal nonsustained supraventricular tachycardia and premature atrial and ventricular.
Genetic determinants contributing to this variation are difficult to study using current mouse models. Acute doxorubicin cardiotoxicity involves cardiomyocyte. Genetic determinants contributing to this variation are difficult to. Cardiomyopathy induced by doxorubicin dox is considered an extremely. 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. Therefore, egcg combined with dox could be useful to scavenge intracellular oxygen free. Doxorubicin induced heart failure can appear very late after the last administration. Fortytwo evaluable endomyocardial biopsies were obtained from 29 patients treated with epirubicin, the 4epimer of doxorubicin in cumulative doses ranging from 147 mgm2 to 888. 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.
Trastuzumab and doxorubicinrelated cardiotoxicity and the. The 6maleimidocaproyl hydrazone derivative of doxorubicin. This high mortality was ascribed to the potentiation of doxorubicin. Liposomal doxorubicinbased chemotherapy was associated with a significant reduction in the risk of cardiotoxicity or 0. The biopsy specimens were examined by light and electron microscopy and were graded. Some trials demonstrated that liposomal doxorubicin reduced cardiotoxicity and had a similar antitumor efficacy compared with conventional anthracycline 10, 11. Cardioprotectors 4 and liposomal preparations with the potential for reduced toxicity relative to free.
Hyperbaric oxygen therapy does not potentiate doxorubicin. The hypothesis proposed was that if doxorubicin cardiotoxicity and hepatotoxicity are related to free radical formation and oxidative stress, an antioxidant such as silymarin may protect. A cumulative treatment dose of 350 mgm2 of free dox shows a. Doxorubicininduced cardiotoxicity in collaborative cross.
Anthracycline cardiotoxicity in the elderly cancer patient annals of. The median cumulative dose for those receiving continuous. It has been shown that free radicals and oxidative stress are involved in doxorubicininduced cardiotoxicity. Antioxidants free fulltext liposomal resveratrol and. Efficacy and cardiotoxicity of liposomal doxorubicinbased. Sexual dimorphism of doxorubicinmediated cardiotoxicity. The incidence of acute cardiotoxicity is approximately 11% 3,4. Annexin v imaging of acute doxorubicin cardiotoxicity. To study the role of myocardial apoptosis following doxorubicin administration, male wistar rats were exposed to 1. Doxorubicin cardiotoxicity can be acute, occurring during and within 23 days of its administration. Despite welldocumented cardiotoxic effects, doxorubicin remains a major anticancer agent.
Subsequent research has led to many other anthracycline. Doxorubicin showed better activity than daunorubicin against mouse tumors, and especially solid tumors. Druginduced mitochondrial dysfunction and cardiotoxicity. Doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. Update on pathophysiology and preventive strategies of.
The anthracyclines and related compounds doxorubicin, daunorubicin, idarubicin, epirubicin, and the anthraquinone mitoxantrone are among the chemotherapeutic agents implicated in. This includes breast cancer, bladder cancer, kaposis sarcoma. This study examined the cardioprotective effects of carvedilol car andor resveratrol res and liposomal res lipores against doxinduced cardiomyopathy, pointing to. Reduction of doxorubicin cardiotoxicity by prolonged. Oct 19, 2012 cytostatic antibiotics of the anthracycline class are the best known of the chemotherapeutic agents that cause cardiotoxicity. Doxorubicin hydrochloride for injection, usp 3 doxorubicin.
Green tea catechinbased complex micelles combined with. Antioxidants free fulltext liposomal resveratrol andor. The hypothesis proposed was that if doxorubicin cardiotoxicity and hepatotoxicity are related to free radical formation and oxidative stress, an antioxidant such as silymarin may protect against doxorubicininduced toxicity in the heart and liver. Cardiotoxicity of chemotherapeutic agents springerlink. Breast cancer doxorubicin 5060 mgm2 46 cycles epirubicin 75100 mgm2 48 cycles increased cardiotoxicity with trastuzumab 11 bolus over 15 min sarcoma doxorubicin 7590.
Cardiotoxicity and exercise wonders, reigle 19 the completion of dox treatment38 and often manifests as dilated cardiomyopathy,36 characterized by hypotension, tachycardia, cardiac dilation,36 and decreased leftventricular ejection fraction. Doxorubicin caused a significant p doxorubicin dox is a widely used chemotherapeutic agent with known cardiotoxic properties, while calorie restriction cr and exercise have welldocumented cardioprotective effects. Doxorubicininduced cardiotoxicity in collaborative cross cc. 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.
Dec 31, 2019 doxorubicin hydrochloride injection, usp is a sterile, isotonic, preservative free solution for intravenous use. The ability of ants to induce ros formation could be predicted from their chemical structure, which contains a quinone moiety fig. Previous studies showed the importance of ampk in the cardiotoxicity of anthracyclines, but these were conducted only in males. Cardiotoxicity accounted for 45% of all drugs withdrawn between 1994 and 2006, which was due mainly to cardiac ischemiarelated and arrhythmogenic side effects. It is available in 5 ml 10 mg, 10 ml 20 mg and 25 ml 50 mg single dose vials and 100 ml 200 mg multiple dose vials. Doxorubicin, sold under the brand name adriamycin among others, is a chemotherapy medication used to treat cancer. Molecular mechanisms of doxorubicininduced cardiotoxicity.
Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. Therefore, there is a clinical need for noninvasive investigation of early. Enzymatic electron reduction of doxorubicin by a variety of oxidases, reductases and dehydrogenases generates highly reactive species including the hydroxyl free radical oh. Alkylating agents such as cyclophosphamide, ifosfamide, cisplatin, carmustine, busulfan, chlormethine and mitomycin have also been associated with cardiotoxicity. Prevention of anthracyclineinduced cardiotoxicity jacc. Doxorubicin cardiotoxicity is associated with the generation of free radicals, and involves not only lipid peroxidation but also a decreased biosynthesis of highly unsaturated fatty acids, leading. Free radical formation has been implicated in doxorubicin cardiotoxicity by means of cu ii and fe iii reduction at the cellular level. Interpatient variability clearance reduced in obese patients i.
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