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Supportive Care in Cancer : Official... Jul 1996The dose-limiting toxicity of the widely used anticancer agent, doxorubicin, is a destructive, irreversible and progressive cardiomyopathy. Prevention of this... (Review)
Review
The dose-limiting toxicity of the widely used anticancer agent, doxorubicin, is a destructive, irreversible and progressive cardiomyopathy. Prevention of this cardiotoxicity without reduction of antitumour efficacy or the production of new toxicities has therefore been a long-time therapeutic goal. It has now been largely achieved by prior administration of dexrazoxane (DXRz; Cardioxane in Europe; Zinecard in North America; ICRF 187). Six randomized, controlled clinical trials in breast and lung cancer and in soft tissue sarcomas of children have shown a 90% reduction in doxorubicin-induced cardiotoxicity. The results of all these trials lead to the conclusion that DXRz permits: (1) cardiotoxic doses of doxorubicin to be given without cardiotoxicity; (2) patients with increased cardiac risk factors to be treated with full doses of dioxorubicin; (3) second-line treatment with other cardiotoxic drugs.
Topics: Adult; Antibiotics, Antineoplastic; Cardiomyopathies; Cardiovascular Agents; Child; Child, Preschool; Clinical Trials as Topic; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Male; Neoplasms; Razoxane; Treatment Outcome
PubMed: 8829310
DOI: 10.1007/BF01358885 -
PloS One 2023Apart from cardiotoxicity, the chemotherapeutic agent doxorubicin (DOX) provokes acute and long-term vascular toxicity. Dexrazoxane (DEXRA) is an effective drug for...
Apart from cardiotoxicity, the chemotherapeutic agent doxorubicin (DOX) provokes acute and long-term vascular toxicity. Dexrazoxane (DEXRA) is an effective drug for treatment of DOX-induced cardiotoxicity, yet it remains currently unknown whether DEXRA prevents vascular toxicity associated with DOX. Accordingly, the present study aimed to evaluate the protective potential of DEXRA against DOX-related vascular toxicity in a previously-established in vivo and ex vivo model of vascular dysfunction induced by 16 hour (h) DOX exposure. Vascular function was evaluated in the thoracic aorta in organ baths, 16h after administration of DOX (4 mg/kg) or DOX with DEXRA (40 mg/kg) to male C57BL6/J mice. In parallel, vascular reactivity was evaluated after ex vivo incubation (16h) of murine aortic segments with DOX (1 μM) or DOX with DEXRA (10 μM). In both in vivo and ex vivo experiments, DOX impaired acetylcholine-stimulated endothelium-dependent vasodilation. In the ex vivo setting, DOX additionally attenuated phenylephrine-elicited vascular smooth muscle cell (VSMC) contraction. Importantly, DEXRA failed to prevent DOX-induced endothelial dysfunction and hypocontraction. Furthermore, RT-qPCR and Western blotting showed that DOX decreased the protein levels of topoisomerase-IIβ (TOP-IIβ), a key target of DEXRA, in the heart, but not in the aorta. Additionally, the effect of N-acetylcysteine (NAC, 10 μM), a reactive oxygen species (ROS) scavenger, was evaluated ex vivo. NAC did not prevent DOX-induced impairment of acetylcholine-stimulated vasodilation. In conclusion, our results show that DEXRA fails to prevent vascular toxicity resulting from 16h DOX treatment. This may relate to DOX provoking vascular toxicity in a ROS- and TOP-IIβ-independent way, at least in the evaluated acute setting. However, it is important to mention that these findings only apply to the acute (16h) treatment period, and further research is warranted to delineate the therapeutic potential of DEXRA against vascular toxicity associated with longer-term repetitive DOX dosing.
Topics: Mice; Animals; Male; Dexrazoxane; Reactive Oxygen Species; Cardiotoxicity; Acetylcholine; Doxorubicin; Mice, Inbred C57BL; Myocytes, Cardiac; Antibiotics, Antineoplastic
PubMed: 38015959
DOI: 10.1371/journal.pone.0294848 -
Mutagenesis Mar 2016Dexrazoxane is the only clinically approved cardioprotectant against anthracyclines-induced cardiotoxicity. Thus, detailed evaluation of the genotoxic potential of...
Dexrazoxane is the only clinically approved cardioprotectant against anthracyclines-induced cardiotoxicity. Thus, detailed evaluation of the genotoxic potential of dexrazoxane and anthracyclines combination is essential to provide more insights into genotoxic and anti-genotoxic alterations that may play a role in the development of the secondary malignancies after treatment with anthracyclines. Thus, our aim was to determine whether non-genotoxic doses of dexrazoxane in combination with the anthracycline, epirubicin can modulate epirubicin-induced genotoxicity and apoptosis in somatic cells. Bone marrow micronucleus test complemented with fluorescence in situ hybridization assay and comet assay were performed to assess the genotoxicity of dexrazoxane and/or epirubicin. Apoptosis was analysed by using the annexin V assay and the occurrence of the hypodiploid DNA content. Generation of reactive oxygen species was also assessed in bone marrow by using the oxidant-sensing fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate. Dexrazoxane was neither genotoxic nor apoptogenic in mice at a single dose of 75 or 150mg/kg. Moreover, it has been shown that dexrazoxane affords significant protection against epirubicin-induced genotoxicity and apoptosis in the bone marrow cells in a dose-dependent manner. Epirubicin induced marked generation of intracellular reactive oxygen species and prior administration of dexrazoxane ahead of epirubicin challenge ameliorated accumulation of these free radicals. It is thus concluded that dexrazoxane can be safely combined with epirubicin and that pre-treatment with dexrazoxane attenuates epirubicin-induced generation of reactive oxygen species and subsequent genotoxicity and apoptosis. Thus, epirubicin-induced genotoxicity can be effectively mitigated by using dexrazoxane.
Topics: Animals; Antineoplastic Agents; Apoptosis; Bone Marrow Cells; Carcinogens; Cardiotonic Agents; Comet Assay; DNA Breaks; Dexrazoxane; Epirubicin; Male; Mice; Micronuclei, Chromosome-Defective; Micronucleus Tests; Mutagenicity Tests; Reactive Oxygen Species
PubMed: 26399706
DOI: 10.1093/mutage/gev065 -
Journal of Pediatric Oncology Nursing :... Apr 1997
Review
Topics: Antibiotics, Antineoplastic; Cardiovascular Agents; Heart Diseases; Humans; Razoxane
PubMed: 9144979
DOI: 10.1177/104345429701400208 -
JACC. CardioOncology Sep 2019The authors performed a systematic review and meta-analysis of randomized and nonrandomized trials on the efficacy of dexrazoxane in patients with breast cancer who were...
OBJECTIVES
The authors performed a systematic review and meta-analysis of randomized and nonrandomized trials on the efficacy of dexrazoxane in patients with breast cancer who were treated with anthracyclines with or without trastuzumab.
BACKGROUND
Breast cancer treatment with anthracyclines and trastuzumab is associated with an increased risk of cardiotoxicity. Among the various strategies to reduce the risk of cardiotoxicity, dexrazoxane is an option for primary prevention, but it is seldom used in clinical practice.
METHODS
Online databases were searched from January 1990 up to March 1, 2019, for clinical trials on the use of dexrazoxane for the prevention of cardiotoxicity in patients with breast cancer receiving anthracyclines with or without trastuzumab. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model meta-analysis.
RESULTS
Seven randomized trials and 2 retrospective trials with a total of 2,177 patients were included. Dexrazoxane reduced the risk of clinical heart failure (RR: 0.19; 95% CI: 0.09 to 0.40; p < 0.001) and cardiac events (RR: 0.36; 95% CI: 0.27 to 0.49; p < 0.001) irrespective of previous exposure to anthracyclines. The rate of a partial or complete oncological response, overall survival, and progression-free survival were not affected by dexrazoxane.
CONCLUSIONS
Dexrazoxane reduced the risk of clinical heart failure and cardiac events in patients with breast cancer undergoing anthracycline chemotherapy with or without trastuzumab and did not significantly impact cancer outcomes. However, the quality of available evidence is low, and further randomized trials are warranted before the systematic implementation of this therapy in clinical practice.
PubMed: 34396164
DOI: 10.1016/j.jaccao.2019.08.003 -
Journal of Pediatric Hematology/oncology Mar 2023Doxorubicin leads to dose dependent cardiotoxicity in childhood acute lymphoblastic leukemia (ALL) survivors. We investigated survivors' heart health using...
INTRODUCTION
Doxorubicin leads to dose dependent cardiotoxicity in childhood acute lymphoblastic leukemia (ALL) survivors. We investigated survivors' heart health using echocardiography and evaluated doxorubicin and dexrazoxane treatments on cardiac function.
METHODS
A total of 196 childhood ALL survivors were stratified (standard risk [SR], high risk with and without dexrazoxane (HR+DEX and HR). We performed a complete transthoracic echocardiographic assessment with M-mode echocardiography, Doppler, and Tissue Doppler. We used 2-dimensional and 3-dimensional echocardiography to measure the left ventricular ejection fraction, whereas myocardial strain imaging was used to obtain global strain indices.
RESULTS
Although most cardiac and arterial dimension parameters were not different between groups, a difference was observed in posterior intima of the right carotid ( P =0.017). Diastolic functions analyses reported that LV shortening fraction and left and right ventricular lateral S' wave amplitudes were lower in HR than in SR and HR+DEX groups ( P =0.028, P =0.048, and P =0.005, respectively). The LV lateral E' in diastolic function was lower in the HR than in SR and HR+DEX groups ( P =0.036). The LV end-systolic wall stress was higher in HR than in SR and HR+DEX groups ( P =0.009). A decrease contractility was observed, while the effect was not group specific. Strain rate was not different between groups, as opposed to tissue Doppler measurements.
CONCLUSIONS
This study showed that dexrazoxane treatments could limit subclinical cardiac dysfunction in childhood ALL survivors, whereas survivors in HR group who did not receive dexrazoxane had potential subclinical cardiac damage observable in heart failure patients. Echocardiographic screening for survivors must be part of the follow-up routine in cardio-oncology.
Topics: Humans; Dexrazoxane; Stroke Volume; Ventricular Function, Left; Doxorubicin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survivors; Cardiotoxicity; Ventricular Dysfunction, Left
PubMed: 36161876
DOI: 10.1097/MPH.0000000000002538 -
Reproduction (Cambridge, England) Oct 2015Infertility induced by anti-cancer treatments pose a major concern for cancer survivors. Doxorubicin (DXR) has been previously shown to exert toxic effects on the...
Infertility induced by anti-cancer treatments pose a major concern for cancer survivors. Doxorubicin (DXR) has been previously shown to exert toxic effects on the testicular germinal epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), we studied its potential effect in reducing DXR-induced testicular toxicity. Male mice were injected with 5 mg/kg DXR, 100 mg/kg DEX, combination of both or saline (control) and sacrificed either 1, 3 or 6 months later. Testes were excised and further processed. Glutathione and apoptosis assays were performed to determine oxidative stress. Immunohistochemistry and confocal microscopy were used to study the effects of the drugs on testicular histology and on spermatogonial reserve. DXR and the combined treatment induced a striking decline in testicular weight. DEX prevented DXR-induced oxidative stress, but enhanced DXR-induced apoptosis within the testes. Furthermore, the combined treatment depleted the spermatogonial reserve after 1 month, with impaired recovery at 3 and 6 months post-treatment. This resulted in compromised sperm parameters, testicular and epididymal weights as well as significantly reduced sperm motility, all of which were more severe than those observed in DXR-treated mice. The activity of DEX in the testis may differ from its activity in cardiomyocytes. Adding DEX to DXR exacerbates DXR-induced testicular toxicity.
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Apoptosis; Cell Proliferation; Dexrazoxane; Doxorubicin; Epididymis; Glutathione; Male; Mice; Mice, Inbred ICR; Organ Size; Oxidative Stress; Sperm Motility; Spermatogonia; Testicular Diseases; Testis
PubMed: 26329125
DOI: 10.1530/REP-15-0129 -
Clinical Cancer Research : An Official... Jul 2021Doxorubicin cardiac toxicity is widely misunderstood, largely preventable, and starts with the first dose. This article reviews the history of doxorubicin cardiac...
Doxorubicin cardiac toxicity is widely misunderstood, largely preventable, and starts with the first dose. This article reviews the history of doxorubicin cardiac toxicity and strategies for minimizing it. Dexrazoxane cardioprotection can safely be initiated on day 1 without compromising antitumor activity, allowing doxorubicin administration beyond the reported maximum lifetime dose..
Topics: Cardiotoxicity; Dexrazoxane; Doxorubicin; Humans; Razoxane; Sarcoma
PubMed: 33990361
DOI: 10.1158/1078-0432.CCR-21-1376 -
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 -
Cancer Feb 2022The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials.
METHODS
P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana-Farber Cancer Institute 95-01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow-up events were assessed with cumulative incidence, Cox regression, and Fine-Gray methods.
RESULTS
In randomized trials (cumulative prescribed doxorubicin dose, 100-360 mg/m ; median follow-up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63-1.13), second cancers (HR, 1.19; 95% CI, 0.62-2.30), all-cause mortality (HR, 1.07; 95% CI, 0.78-1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41-5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450-600 mg/m ; median follow-up, 16.6-18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20-year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m ) was 1.6% (vs 0% in P9754; P = .13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P = .02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P = .35).
CONCLUSIONS
Dexrazoxane did not appear to adversely affect long-term mortality, event-free survival, or second cancer risk.
Topics: Child; Dexrazoxane; Doxorubicin; Follow-Up Studies; Hodgkin Disease; Humans; Outcome Assessment, Health Care; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 34644414
DOI: 10.1002/cncr.33974