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Expert Review of Cardiovascular Therapy Nov 2008Dexrazoxane is a derivative of the powerful metal-chelating agent ethyl enediamine tetra acetic acid. Its cardioprotective effect is thought to be due to its ability to... (Review)
Review
Dexrazoxane is a derivative of the powerful metal-chelating agent ethyl enediamine tetra acetic acid. Its cardioprotective effect is thought to be due to its ability to chelate iron and reduce the number of metal ions complexed with anthracycline and, consequently, decrease the formation of superoxide radicals. Preclinical studies have confirmed that dexrazoxane has significant activity as a cardioprotective agent against anthracycline-induced cardiotoxicity. Dexrazoxane is well-tolerated, with myelosuppression being the dose-limiting toxicity in Phase I trials. The cardioprotective utility of dexrazoxane has been further illustrated in a number of randomized trials. In addition no significant difference in survival has been observed between the dexrazoxane and control arms of these trials but, in one, a significantly lower response rate was observed in the dexrazoxane compared to placebo arm. Further trials are required to evaluate the efficacy of dexrazoxane in hematological malignancies as well as the adjuvant treatment of breast cancer. Its use in the paediatric setting and in the management of elderly patients with cardiac comorbidity also requires investigation. Recently, interest has focused on the use of dexrazoxane as an antidote for anthracycline extravasation. In addition the general cytoprotective activity of this drug requires further assessment, as well as selectivity in this context.
Topics: Aged; Animals; Anthracyclines; Antibiotics, Antineoplastic; Bone Marrow; Cardiotonic Agents; Chelating Agents; Child; Clinical Trials as Topic; Drug Evaluation, Preclinical; Heart Diseases; Humans; Neoplasms; Razoxane
PubMed: 19018683
DOI: 10.1586/14779072.6.10.1311 -
World Journal of Clinical Oncology Feb 2016Chemotherapy extravasation remains an accidental complication of chemotherapy administration and may result in serious damage to patients. We review in this article the... (Review)
Review
Chemotherapy extravasation remains an accidental complication of chemotherapy administration and may result in serious damage to patients. We review in this article the clinical aspects of chemotherapy extravasation and latest advances in definitions, classification, prevention, management and guidelines. We review the grading of extravasation and tissue damage according to various chemotherapeutic drugs and present an update on treatment and new antidotes including dexrazoxane for anthracyclines extravasation. We highlight the importance of education and training of the oncology team for prevention and prompt pharmacological and non-pharmacological management and stress the availability of new antidotes like dexrazoxane wherever anthracyclines are being infused.
PubMed: 26862492
DOI: 10.5306/wjco.v7.i1.87 -
Current Pharmaceutical Biotechnology Aug 2012The cumulative cardiac toxicity of the anthracycline antibiotics and their propensity to produce severe tissue injury following extravasation from a peripheral vein... (Review)
Review
The cumulative cardiac toxicity of the anthracycline antibiotics and their propensity to produce severe tissue injury following extravasation from a peripheral vein during intravenous administration remain significant problems in clinical oncologic practice. Understanding of the free radical metabolism of these drugs and their interactions with iron proteins led to the development of dexrazoxane, an analogue of EDTA with intrinsic antineoplastic activity as well as strong iron binding properties, as both a prospective cardioprotective therapy for patients receiving anthracyclines and as an effective treatment for anthracycline extravasations. In this review, the molecular mechanisms by which the anthracyclines generate reactive oxygen species and interact with intracellular iron are examined to understand the cardioprotective mechanism of action of dexrazoxane and its ability to protect the subcutaneous tissues from anthracycline-induced tissue necrosis.
Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Cardiotonic Agents; Extravasation of Diagnostic and Therapeutic Materials; Heart Diseases; Humans; Injections, Intravenous; Iron; Razoxane; Reactive Oxygen Species
PubMed: 22352729
DOI: 10.2174/138920112802273245 -
Future Oncology (London, England) Feb 2006Accidental extravasation injury from the use of the anthracycline anticancer drugs doxorubicin, daunorubicin, epirubicin and idarubicin can be a serious complication of... (Review)
Review
Accidental extravasation injury from the use of the anthracycline anticancer drugs doxorubicin, daunorubicin, epirubicin and idarubicin can be a serious complication of their use. As yet, there is little consensus on the way that anthracycline extravasation injury should be clinically managed. Dexrazoxane, which is currently clinically used to reduce doxorubicin-induced cardiotoxicity, has also been shown in preclinical studies to be highly efficacious in preventing anthracycline-induced extravasation injury. Several clinical case reports of dexrazoxane for this use have also indicated positive outcomes. There are currently two multicenter Phase II/III clinical trials underway. Dexrazoxane is a prodrug analog of the metal chelator EDTA that most likely acts by removing iron from the iron-doxorubicin complex, thus preventing formation of damaging reactive oxygen species.
Topics: Anthracyclines; Clinical Trials as Topic; Edetic Acid; Extravasation of Diagnostic and Therapeutic Materials; Molecular Structure; Razoxane
PubMed: 16556068
DOI: 10.2217/14796694.2.1.15 -
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 -
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 -
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 -
Biomedicine & Pharmacotherapy =... Dec 2022Doxorubicin (DOX), as a kind of chemotherapy agent with remarkable therapeutic effect, can be used to treat diverse malignant tumors clinically. Dose-dependent... (Review)
Review
Doxorubicin (DOX), as a kind of chemotherapy agent with remarkable therapeutic effect, can be used to treat diverse malignant tumors clinically. Dose-dependent cardiotoxicity is the most serious adverse reaction after DOX treatment, which eventually leads to cardiomyopathy and greatly limits the clinical application of DOX. DOX-induced cardiomyopathy is not a result of a single mechanistic action, and multiple mechanisms have been discovered and demonstrated experimentally, such as oxidative stress, inflammation, mitochondrial damage, calcium homeostasis disorder, ferroptosis, autophagy and apoptosis. Dexrazoxane (DEX) is the only protective agent approved by FDA for the treatment of DOX cardiomyopathy, but its clinical treatment still has some limitations. Therefore, we need to find other effective therapeutic drugs as soon as possible. In this paper, the drugs that effectively improve cardiomyopathy in recent years are mainly described from the aspects of natural drugs, endogenous substances, new dosage forms, herbal medicines, chemical modification and marketed drugs. The aim of the present study is to evaluate the effects of these drugs on DOX-induced anticancer and cardiomyopathy curative effects, so as to provide some reference value for clinical treatment of DOX-induced cardiomyopathy in the future.
Topics: Humans; Myocytes, Cardiac; Cardiotoxicity; Doxorubicin; Cardiomyopathies; Apoptosis; Oxidative Stress
PubMed: 36279722
DOI: 10.1016/j.biopha.2022.113903 -
Journal of Clinical Oncology : Official... Aug 2015
Topics: Dexrazoxane; Female; Hodgkin Disease; Humans; Male; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 26195707
DOI: 10.1200/JCO.2015.61.7928 -
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