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Open Heart 2019We sought to determine how sex and dexrazoxane therapy influence cardiac remodelling in children with sarcoma receiving high-dose doxorubicin.
OBJECTIVE
We sought to determine how sex and dexrazoxane therapy influence cardiac remodelling in children with sarcoma receiving high-dose doxorubicin.
METHODS
In a retrospective cohort of 85 children with sarcoma receiving high-dose doxorubicin, echocardiography measures prior to, early after (within 6 months of doxorubicin completion) and 1 - 2 years after doxorubicin completion were quantified. At each follow-up visit, multivariable, propensity-adjusted linear regression models evaluated dexrazoxane's effects on changes in left ventricular (LV) shortening fraction (SF), structure, strain and wall stress for subgroups divided by sex. Likelihood ratio tests assessed the interaction between sex and dexrazoxane in determining these changes.
RESULTS
Early after doxorubicin completion, males not treated with dexrazoxane (n = 15) developed increased cavity size and diminished circumferential strain; females (n = 8) developed diminished SF and strain indices, and increased cavity size and wall stress. With dexrazoxane, males (n = 33) demonstrated less deterioration in circumferential strain by 3.4% (95% CI 0.01 to 6.8), and females (n = 29) demonstrated less reduction in SF by 5.7% (95% CI 2.1 to 9.3), and had mitigation of increases in cavity size and wall stress. In interaction analyses, females had greater protection with dexrazoxane with regard to SF (p = 0.019) and cavity size in diastole (p = 0.002) and systole (p ≤ 0.001). These findings largely persisted 1 - 2 years after doxorubicin therapy.
CONCLUSIONS
Early, sustained alterations in LV structure and function occur in children with sarcoma after high-dose doxorubicin, with adverse changes and protective effects of dexrazoxane more pronounced in females as compared with males. Dexrazoxane may have sex-specific cardioprotective effects.
PubMed: 31297226
DOI: 10.1136/openhrt-2019-001025 -
Anti-cancer Drugs Oct 2018The extravasation of chemotherapeutic agents is a challenge for oncologic care teams. The management of nonliposomal (conventional) anthracyclines is well established in... (Review)
Review
The extravasation of chemotherapeutic agents is a challenge for oncologic care teams. The management of nonliposomal (conventional) anthracyclines is well established in clinical practice guidelines, including general measures and specific antidotes, such as dexrazoxane. However, there is little scientific evidence on the management of liposomal and pegylated liposomal anthracyclines. The aim of this paper was to review the scientific literature on the extravasation of liposomal and pegylated liposomal anthracyclines and determine the clinical impact of this type of extravasation, focusing on dexrazoxane. The literature was searched using two databases: PubMed and Embase. Three searches were conducted, using liposomal anthracycline extravasation, pegylated liposomal anthracycline extravasation, and liposomal doxorubicin extravasation as keywords, respectively. Seven articles fulfilled the study eligibility criteria and included seventeen cases in humans. Extravasation occurred with three drugs: liposomal doxorubicin in nine (53%) patients, liposomal daunorubicin in four (23.5%) patients, and pegylated liposomal doxorubicin in four (23.5%) patients. General measures for extravasations were applied in all patients, but only three patients received dexrazoxane. All cases were completely resolved at 2-3 months, except for one patient, in whom dexrazoxane was not used. In animals, dexrazoxane decreased both the frequency of wounds produced by pegylated liposomal doxorubicin and their extent. The pharmacokinetic profiles of liposomal and pegylated liposomal anthracyclines differ from those of conventional anthracyclines, modifying their effectiveness and safety. General measures may be inadequate to heal areas affected by extravasation, which may require the administration of dexrazoxane. However, each case should be evaluated individually for the administration of dexrazoxane in off-label use until scientific evidence is available on its effectiveness and safety as an antidote for these formulations of anthracyclines.
Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Daunorubicin; Dexrazoxane; Doxorubicin; Extravasation of Diagnostic and Therapeutic Materials; Humans; Liposomes; Polyethylene Glycols
PubMed: 30036190
DOI: 10.1097/CAD.0000000000000672 -
BioMed Research International 2020The usage of doxorubicin is hampered by its life-threatening cardiotoxicity in clinical practice. Dexrazoxane is the only cardioprotective medicine approved by the FDA...
The usage of doxorubicin is hampered by its life-threatening cardiotoxicity in clinical practice. Dexrazoxane is the only cardioprotective medicine approved by the FDA for preventing doxorubicin-induced cardiac toxicity. Nevertheless, the mechanism of dexrazoxane is incompletely understood. The aim of our study is to investigate the possible molecular mechanism of dexrazoxane against doxorubicin-induced cardiotoxicity. We established a doxorubicin-induced mouse and cardiomyocyte injury model. Male C57BL/6J mice were randomly distributed into a control group (Con), a doxorubicin treatment group (DOX), a doxorubicin plus dexrazoxane treatment group (DOX+DEX), and a dexrazoxane treatment group (DEX). Echocardiography and histology analyses were performed to evaluate heart function and structure. DNA laddering, qRT-PCR, and Western blot were performed on DOX-treated cardiomyocytes with/without DEX treatment in vitro. Cardiomyocytes were then transfected with miR-17-5p mimics or inhibitors in order to analyze its downstream target. Our results demonstrated that dexrazoxane has a potent effect on preventing cardiac injury induced by doxorubicin in vivo and in vitro by reducing cardiomyocyte apoptosis. MicroRNA plays an important role in cardiovascular diseases. Our data revealed that dexrazoxane could upregulate the expression of miR-17-5p, which plays a cytoprotective role in response to hypoxia by regulating cell apoptosis. Furthermore, the miRNA and protein analysis revealed that miR-17-5p significantly attenuated phosphatase and tensin homolog (PTEN) expression in cardiomyocytes exposed to doxorubicin. Taken together, dexrazoxane might exert a cardioprotective effect against doxorubicin-induced cardiomyocyte apoptosis by regulating the expression of miR-17-5p/PTEN cascade.
Topics: Animals; Apoptosis; Cardiotoxicity; Cell Survival; Dexrazoxane; Disease Models, Animal; Doxorubicin; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Myocytes, Cardiac; PTEN Phosphohydrolase; Protective Agents; Up-Regulation
PubMed: 32190669
DOI: 10.1155/2020/5107193 -
Biochemical and Biophysical Research... Feb 2020Doxorubicin, as a first line chemotherapeutic agent, its usage is limited owing to cardiotoxicity. Necroptosis is a new form of programmed cell death, and recent...
Doxorubicin, as a first line chemotherapeutic agent, its usage is limited owing to cardiotoxicity. Necroptosis is a new form of programmed cell death, and recent investigations indicated that necroptosis is vitally involved in serious cardiac pathological conditions. Dexrazoxane is the only cardiac protective drug approved by FDA for anthracycline. We aimed to explore whether and how dexrazoxane regulates doxorubicin-induced cardiomyocyte necroptosis. First, doxorubicin could cause heart failure and reduce cardiomyocyte viability by promoting cell apoptosis and necroptosis in vivo and in vitro. Second, necroptosis plays an important role in doxorubicin induced cardiomyocyte injury, which could be inhibited by Nec-1. Third, dexrazoxane increased cell viability and protect heart function by decreasing both cardiomyocyte apoptosis and necroptosis after doxorubicin treatment. Forth, dexrazoxane attenuated doxorubicin-induced inflammation and necroptosis by the inhibition of p38MAPK/NF-κB pathways. These results indicated that dexrazoxane ameliorates cardiotoxicity and protects heart function by attenuating both apoptosis and necroptosis in doxorubicin induced cardiomyocyte injury.
Topics: Animals; Apoptosis; Cells, Cultured; Dexrazoxane; Dose-Response Relationship, Drug; Doxorubicin; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Necroptosis; Structure-Activity Relationship
PubMed: 31837803
DOI: 10.1016/j.bbrc.2019.12.027 -
Expert Opinion on Investigational Drugs Feb 2008The use of the anthracycline anticancer drugs doxorubicin, daunorubicin, epirubicin and idarubicin sometimes results in accidental extravasation injury and can be a... (Review)
Review
BACKGROUND
The use of the anthracycline anticancer drugs doxorubicin, daunorubicin, epirubicin and idarubicin sometimes results in accidental extravasation injury and can be a serious complication of their use.
OBJECTIVE
The object of this review was to evaluate the preclinical and clinical literature on the use of dexrazoxane in preventing anthracycline-induced extravasation injury.
METHODS
A review of the literature was carried out using PubMed.
RESULTS/CONCLUSIONS
Dexrazoxane, which is clinically used to reduce doxorubicin-induced cardiotoxicity, has been shown in two clinical studies and in several case reports to be highly efficacious in preventing anthracycline-induced extravasation injury. Dexrazoxane is a prodrug analog of the metal chelator EDTA that likely acts by removing iron from the iron-anthracycline complex, thus preventing formation of damaging reactive oxygen species.
Topics: Animals; Anthracyclines; Antineoplastic Agents; Cardiotonic Agents; Extravasation of Diagnostic and Therapeutic Materials; Humans; Razoxane
PubMed: 18230055
DOI: 10.1517/13543784.17.2.217 -
Expert Review of Anticancer Therapy Aug 2007Accidental extravasation of anthracycline-containing anticancer chemotherapy is a feared complication that may lead to progressive tissue damage. The condition may... (Review)
Review
Accidental extravasation of anthracycline-containing anticancer chemotherapy is a feared complication that may lead to progressive tissue damage. The condition may require extensive surgical intervention and often has severe long-term effects. Until a short while ago, there has been no effective treatment against the devastating effect of extravasated anthracycline. However, dexrazoxane has proven highly effective in preventing necrosis in both preclinical and clinical studies and is now approved in Europe (Savene), and has orphan drug status in the USA (Totect) for this indication. Hence, it is the first and only proven effective antidote against anthracycline extravasation injuries.
Topics: Anthracyclines; Antineoplastic Agents; Chelating Agents; Clinical Trials as Topic; Humans; Razoxane; Skin Diseases
PubMed: 18028016
DOI: 10.1586/14737140.7.8.1081 -
Expert Opinion on Drug Metabolism &... Aug 2017With advances in clinical oncology, the burden of morbidity and mortality for cancer survivors due to the cardiac side effects of the chemotherapy is steadily... (Review)
Review
With advances in clinical oncology, the burden of morbidity and mortality for cancer survivors due to the cardiac side effects of the chemotherapy is steadily increasing. Treatment-related cardiac damage is progressive and often irreversible. Primary prevention of cardiotoxicity during treatment is possible with strategies like limiting the cumulative anthracycline dose, the use of anthracycline structural analogs, and especially cardioprotective agents. Areas covered: This review covers the various cardiotoxic chemotherapeutic agents, the pathophysiology of cardiotoxicity due to anthracyclines, and the clinical and subclinical presentations and progression of childhood anthracycline cardiotoxicity. We also discuss preventive measures and strategies, especially the cardioprotectant agent dexrazoxane where there is strong evidence-based support for its use with anthracycline chemotherapy. However, there is a paucity of evidence-based recommendations for diagnosing and treating cancer therapy-induced cardiovascular complications. Finally, we discuss the potential of cardio-oncology. Expert opinion: There is no 'safe' anthracycline dose if the goal is normal long-term cardiovascular status but higher lifetime cumulative doses of anthracyclines, higher dose rates, female sex, longer follow-up, younger age at anthracycline treatment, pre-existing cardiovascular disease, and cardiac irradiation are associated with more severe cardiotoxicity. With deeper understanding of the mechanisms of the adverse cardiac effects and identification of driver mutations causing these effects, personalized cancer therapy to limit cardiotoxic effects can be achieved, such as with the cardioprotectant dexrazoxane.
Topics: Animals; Anthracyclines; Antineoplastic Agents; Cardiotonic Agents; Cardiotoxicity; Child; Dexrazoxane; Dose-Response Relationship, Drug; Female; Humans; Male; Neoplasms; Primary Prevention; Risk Factors
PubMed: 28679288
DOI: 10.1080/17425255.2017.1351547 -
JACC. CardioOncology Sep 2019
PubMed: 34396165
DOI: 10.1016/j.jaccao.2019.08.011 -
Mini Reviews in Medicinal Chemistry 2017The anthracycline doxorubicin (DOX) has proved to be one of the most widely used and most effective antitumor drugs since its emergence in the 1960s. However, the... (Review)
Review
INTRODUCTION
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. However, the utility of DOX is compromised by its potential lethal cardiotoxicity. In this review we summarize development in prevention and management of DOX-induced cardiotoxicity comprehensively.
BACKGROUND
Strategies to enhance DOX efficacy in cancer cells while minimizing associated cardiotoxicity may prove clinically valuable. Employment of DOX derivatives, including currently available mitoxantrone and epirubicin, has been testified in several clinical trials. Several cardioprotective agents, including dexrazoxane, statins, angiotensin-converting enzyme inhibitors, calcium channel blockers, beta-blockers, and etc., have been developed and tested in animal and clinical trials.
CONCLUSION
Several strategies have been reported on the prevention and management of DOX-elicited cardiotoxicity, and many of them await verification from large scale clinical trials. Dexrazoxane has been approved to prevent and treat side effects of DOX, although concerns still exist that it might increase incidence of some kind of malignant tumors. Promising findings in autophagy, RNA binding protein quaking and statins encourage further research developing strategies by which heart protection and cancer cell killing are achieved simutaneously.
Topics: Antibiotics, Antineoplastic; Cardiotonic Agents; Cardiotoxicity; Doxorubicin; Humans; Neoplasms
PubMed: 27337969
DOI: 10.2174/1389557516666160621083659 -
Journal of the National Cancer Institute Apr 2016Several randomized controlled trials (RCTs) have demonstrated that dexrazoxane reduces anthracycline cardiotoxicity in adults, but use in children has been hindered by... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Several randomized controlled trials (RCTs) have demonstrated that dexrazoxane reduces anthracycline cardiotoxicity in adults, but use in children has been hindered by lack of direct evidence of cardioprotection and concerns regarding second malignant neoplasms (SMNs). This study aimed to systematically review the evidence regarding dexrazoxane in children.
METHODS
We searched Medline, Embase, the Cochrane Library, and abstracts for RCTs and nonrandomized studies (NRSs) that compared dexrazoxane to no cardioprotection among children. We combined findings using random-effects models. All statistical tests were two-sided.
RESULTS
Eleven eligible publications reported results from five RCTs (1254 patients), and 15 publications reported results from 12 NRSs (3385 patients). Dexrazoxane did not impact clinical cardiotoxicity in RCTs because of a low cardiotoxic event rate (three events among all patients) but was associated with a reduction in subclinical cardiotoxicity. Among NRSs, dexrazoxane was associated with a reduction in clinical cardiotoxicity (relative risk (RR) = 0.29, P = .001) and clinical+subclinical cardiotoxicity (RR = 0.43, P < .001). Among RCTs, 17 of 635 (2.7%) patients treated with dexrazoxane developed an SMN compared with seven of 619 (1.1%) who did not receive dexrazoxane (RR = 2.37, P = .06). Two RCTs that used concurrent etoposide reported an increased risk of acute myeloid leukemia, while one that used cranial radiation reported an increased risk of brain tumors. Event-free survival did not differ (P = .91).
CONCLUSION
Dexrazoxane is associated with a statistically significant risk reduction for most cardiotoxic outcomes. Dexrazoxane is associated with a statistically borderline increase in SMNs, possibly because of an interaction with concurrent cancer therapies. The decision to use dexrazoxane in children should balance the risks of cardiotoxicity and SMNs specific to each treatment protocol.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Bias; Cardiotonic Agents; Child; Dexrazoxane; Disease-Free Survival; Evidence-Based Medicine; Heart; Heart Diseases; Humans; Incidence; Leukemia, Myeloid, Acute; Neoplasms, Second Primary; Risk; Treatment Outcome
PubMed: 26598513
DOI: 10.1093/jnci/djv357