-
Pharmacotherapy Dec 2021To describe the proposed mechanisms of chemotherapy-associated cardiomyopathy (CAC) and potential cardioprotective therapies for CAC including a comprehensive review of... (Review)
Review
OBJECTIVE
To describe the proposed mechanisms of chemotherapy-associated cardiomyopathy (CAC) and potential cardioprotective therapies for CAC including a comprehensive review of existing systematic analyses, guideline recommendations, and ongoing clinical trials.
DATA SOURCES
A literature search of MEDLINE was performed (from 1990 to June 2020) using the following search terms: anthracycline, trastuzumab, cardiomyopathy, cardiotoxicity, primary prevention, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), beta blocker, dexrazoxane (DEX) as well as using individual names from select therapeutic categories.
STUDY SELECTION AND DATA EXTRACTION
Existing English language systematic analyses and guidelines were considered.
DATA SYNTHESIS
The mechanisms of CAC are multifaceted, but various cardioprotective therapies target many of these pathways. To date, anthracyclines and HER-2 targeted therapies have been the focus of cardioprotective trials to date as they are the most commonly implicated therapies in CAC. While traditional neurohormonal antagonists (ACEIs, ARBs, and beta blockers) and DEX performed favorably in many small clinical trials, the quality of available evidence remains limited. Hence, major guidelines lack consensus on an approach to primary prevention of CAC. Given the uncertain role of preventive therapy, monitoring for a symptomatic or asymptomatic decline in LV function is imperative with prompt evaluation should this occur. Numerous ongoing randomized controlled trials seek to either confirm the findings of these previous studies or identify new therapeutic agents to prevent CAC. Clinical implications are derived from the available literature as well as current guideline recommendations for CAC cardioprotection.
CONCLUSION
At this time, no single therapy has a clear cardioprotective benefit in preventing CAC nor is any therapy strongly recommended by current guidelines. Additional studies are needed to determine the optimal preventative regimens.
Topics: Cardiomyopathies; Cardiotoxicity; Clinical Trials as Topic; Humans
PubMed: 34806206
DOI: 10.1002/phar.2638 -
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 -
JACC. CardioOncology Sep 2021Anthracycline-induced cardiomyopathy (AIC) is a significant source of morbidity and mortality in cancer survivors. The role of mesenchymal stem cells (MSCs) in treating...
BACKGROUND
Anthracycline-induced cardiomyopathy (AIC) is a significant source of morbidity and mortality in cancer survivors. The role of mesenchymal stem cells (MSCs) in treating AIC was evaluated in the SENECA trial, a Phase 1 National Heart, Lung, and Blood Institute-sponsored study, but the mechanisms underpinning efficacy in human tissue need clarification.
OBJECTIVES
The purpose of this study was to perform an in vitro clinical trial evaluating the efficacy and putative mechanisms of SENECA trial-specific MSCs in treating doxorubicin (DOX) injury, using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iCMs) generated from SENECA patients.
METHODS
Patient-specific iCMs were injured with 1 μmol/L DOX for 24 hours, treated with extracellular vesicles (EVs) from MSCs by either coculture or direct incubation and then assessed for viability and markers of improved cellular physiology. MSC-derived EVs were separated into large extracellular vesicles (L-EVs) (>200 nm) and small EVs (<220nm) using a novel filtration system.
RESULTS
iCMs cocultured with MSCs in a transwell system demonstrated improved iCM viability and attenuated apoptosis. L-EVs but not small EVs recapitulated this therapeutic effect. L-EVs were found to be enriched in mitochondria, which were shown to be taken up by iCMs. iCMs treated with L-EVs demonstrated improved contractility, reactive oxygen species production, ATP production, and mitochondrial biogenesis. Inhibiting L-EV mitochondrial function with 1-methyl-4-phenylpyridinium attenuated efficacy.
CONCLUSIONS
L-EV-mediated mitochondrial transfer mitigates DOX injury in patient-specific iCMs. Although SENECA was not designed to test MSC efficacy, consistent tendencies toward a positive effect were observed across endpoints. Our results suggest a mechanism by which MSCs may improve cardiovascular performance in AIC independent of regeneration, which could inform future trial design evaluating the therapeutic potential of MSCs.
PubMed: 34604804
DOI: 10.1016/j.jaccao.2021.05.006 -
Circulation. Heart Failure Nov 2021Anthracycline-induced heart failure has been traditionally attributed to direct iron-catalyzed oxidative damage. Dexrazoxane (DEX)-the only drug approved for its...
BACKGROUND
Anthracycline-induced heart failure has been traditionally attributed to direct iron-catalyzed oxidative damage. Dexrazoxane (DEX)-the only drug approved for its prevention-has been believed to protect the heart via its iron-chelating metabolite ADR-925. However, direct evidence is lacking, and recently proposed TOP2B (topoisomerase II beta) hypothesis challenged the original concept.
METHODS
Pharmacokinetically guided study of the cardioprotective effects of clinically used DEX and its chelating metabolite ADR-925 (administered exogenously) was performed together with mechanistic experiments. The cardiotoxicity was induced by daunorubicin in neonatal ventricular cardiomyocytes in vitro and in a chronic rabbit model in vivo (n=50).
RESULTS
Intracellular concentrations of ADR-925 in neonatal ventricular cardiomyocytes and rabbit hearts after treatment with exogenous ADR-925 were similar or exceeded those observed after treatment with the parent DEX. However, ADR-925 did not protect neonatal ventricular cardiomyocytes against anthracycline toxicity, whereas DEX exhibited significant protective effects (10-100 µmol/L; <0.001). Unlike DEX, ADR-925 also had no significant impact on daunorubicin-induced mortality, blood congestion, and biochemical and functional markers of cardiac dysfunction in vivo (eg, end point left ventricular fractional shortening was 32.3±14.7%, 33.5±4.8%, 42.7±1.0%, and 41.5±1.1% for the daunorubicin, ADR-925 [120 mg/kg]+daunorubicin, DEX [60 mg/kg]+daunorubicin, and control groups, respectively; <0.05). DEX, but not ADR-925, inhibited and depleted TOP2B and prevented daunorubicin-induced genotoxic damage. TOP2B dependency of the cardioprotective effects was probed and supported by experiments with diastereomers of a new DEX derivative.
CONCLUSIONS
This study strongly supports a new mechanistic paradigm that attributes clinically effective cardioprotection against anthracycline cardiotoxicity to interactions with TOP2B but not metal chelation and protection against direct oxidative damage.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Cardiotoxicity; DNA Topoisomerases, Type II; Daunorubicin; Dexrazoxane; Heart Diseases; Heart Failure; Humans; Myocytes, Cardiac; Oxidative Stress; Topoisomerase II Inhibitors
PubMed: 34551586
DOI: 10.1161/CIRCHEARTFAILURE.120.008209 -
Cell Chemical Biology Mar 2022Topoisomerase II (topo II) is essential for disentangling newly replicated chromosomes. DNA unlinking involves the physical passage of one duplex through another and...
Topoisomerase II (topo II) is essential for disentangling newly replicated chromosomes. DNA unlinking involves the physical passage of one duplex through another and depends on the transient formation of double-stranded DNA breaks, a step exploited by frontline chemotherapeutics to kill cancer cells. Although anti-topo II drugs are efficacious, they also elicit cytotoxic side effects in normal cells; insights into how topo II is regulated in different cellular contexts is essential to improve their targeted use. Using chemical fractionation and mass spectrometry, we have discovered that topo II is subject to metabolic control through the TCA cycle. We show that TCA metabolites stimulate topo II activity in vitro and that levels of TCA flux modulate cellular sensitivity to anti-topo II drugs in vivo. Our work reveals an unanticipated connection between the control of DNA topology and cellular metabolism, a finding with ramifications for the clinical use of anti-topo II therapies.
Topics: Antineoplastic Agents; DNA; DNA Topoisomerases, Type II; Topoisomerase II Inhibitors
PubMed: 34529934
DOI: 10.1016/j.chembiol.2021.08.014 -
Saudi Pharmaceutical Journal : SPJ :... Aug 2021Anti-tumour efficacy of doxorubicin is hindered by the cumulative dose-dependent cardiotoxicity induced by reactive oxygen species during its metabolism. As has proven...
Anti-tumour efficacy of doxorubicin is hindered by the cumulative dose-dependent cardiotoxicity induced by reactive oxygen species during its metabolism. As has proven antioxidant potential, objective of this study was to investigate the cardioprotective activity of bark extract against doxorubicin induced cardiotoxicity in Wistar rats. Physicochemical and phytochemical analysis was carried out and dose response effect and the cardioprotective activity of were determined . 180 mg/kg dexrazoxane was used as the positive control. Plant extracts were free of heavy metals and toxic phytoconstituents. study carried out in Wistar rats revealed a significant increase (p < 0.05) in cardiac troponin I, NT-pro brain natriuretic peptide, AST and LDH concentrations in the doxorubicin control group (18 mg/kg) compared to the normal control. Rats pre-treated with the optimum dosage of (2.0 g/kg) showed a significant reduction (p < 0.05) in all above parameters compared to the doxorubicin control. A significant reduction was observed in the total antioxidant capacity, reduced glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase activity while the lipid peroxidation and myeloperoxidase activity were significantly increased in the doxorubicin control group compared to the normal control (p < 0.05). Pre-treatment with bark showed a significant decrease in lipid peroxidation, myeloperoxidase activity and significant increase in rest of the parameters compared to the doxorubicin control (p < 0.05). Histopathological analysis revealed a preserved appearance of the myocardium and lesser degree of cellular changes of necrosis in rats pre-treated with extract. In conclusion, bark extract has the potential to significantly reduce doxorubicin induced oxidative stress and inflammation in Wistar rats.
PubMed: 34408544
DOI: 10.1016/j.jsps.2021.06.004 -
International Journal of Clinical... Nov 2021Adding dexrazoxane to the treatment during neoadjuvant/adjuvant anthracycline-based chemotherapy in patients with breast cancer prevents the development of heart...
INTRODUCTION
Adding dexrazoxane to the treatment during neoadjuvant/adjuvant anthracycline-based chemotherapy in patients with breast cancer prevents the development of heart failure. In this study, we investigated whether dexrazoxane has a protective effect on arrhythmia resulting from chemotherapy.
METHODS
Patients with breast cancer who received neoadjuvant/adjuvant anthracycline-based chemotherapy in the medical oncology polyclinic between 2017 and 2020 were included in the study. To investigate the effect of dexrazoxane on arrhythmia, this retrospective study included 70 patients, whose 12-lead surface electrocardiograms (ECGs) and echocardiography were obtained before receiving anthracycline-based treatment and after receiving four cycles of chemotherapy. Thirty-two patients received anthracycline only, and 38 patients received anthracycline and dexrazoxane. Arrhythmia parameters such as QT interval, QTc interval, Tp-e interval, Tp-e/QT, Tp-e/QTc and frontal QRS-T angle were calculated from 12-lead ECGs.
RESULTS
Arrhythmia parameters such as frontal QRS-T angle , QT , QTc and heart rate were significantly increased after chemotherapy in both the groups that received dexrazoxane and did not receive dexrazoxane (P < .05). Contrary to the ECG parameters, ejection fraction was decreased in the dexrazoxane group (60.5 ± 2.2 vs 60.1 ± 2.0; P = .038) and the other group (60.4 ± 1.3 vs 60.0 ± 2.6; P = .043) after the chemotherapy.
CONCLUSION
This study demonstrated that dexrazoxane may not have a protective effect on ECG parameters which are predictors of arrhythmia, at breast cancer patients who received anthracyclines.
Topics: Anthracyclines; Arrhythmias, Cardiac; Breast Neoplasms; Dexrazoxane; Female; Humans; Neoadjuvant Therapy; Retrospective Studies
PubMed: 34363726
DOI: 10.1111/ijcp.14705 -
Frontiers in Cardiovascular Medicine 2021Dexrazoxane (DXZ) reduces cytotoxicity caused by Doxorubicin (DOX). However, the mechanism of DXZ in ferroptosis and cardiomyopathy remains unclear. This research,...
Dexrazoxane (DXZ) reduces cytotoxicity caused by Doxorubicin (DOX). However, the mechanism of DXZ in ferroptosis and cardiomyopathy remains unclear. This research, therefore, explores the role and mechanism of DXZ in DOX-induced ferroptosis and cardiomyopathy in rats. Kaplan-Meier survival analysis was performed in rats treated by DOX in combination with ferroptosis inhibitor (FER-1) or other cell death-associated inhibitors. The ferroptosis, cardiotoxicity, and expression of high mobility group box 1 (HMGB1) in rats treated by DOX in combination with FER-1 or with DXZ were determined by hematoxylin and eosin staining, echocardiographic analysis, and quantitative real-time PCR. The ferroptosis in DOX-treated rats that received HMGB1 knockdown or overexpression was further detected using molecular experiments. Finally, the viability, level of malondialdehyde (MDA), and expressions of ferroptosis-related markers (PTGS2, GPX4, and FTH1) of rat cardiomyocyte H9c2 exposed to DOX combined with FER-1, zVAD (an apoptosis inhibitor), DXZ, or not were detected by performing molecular experiments. FER-1 increased the survival of the rats induced by DOX. The DOX-induced ferroptosis and cardiotoxicity could be reversed by FER-1 or DXZ. HMGB1 was induced by DOX but was inhibited by DXZ or FER-1. Overexpression of HMGB1 promoted the ferroptosis and cardiotoxicity induced by DOX in the rats although silencing of HMGB1 showed opposite effects. The data indicate that DOX suppressed the viability and increased the MDA level in H9c2 cells in a dose-dependent manner. Moreover, DOX-induced increase of PTGS2 and decrease of GPX4 and FTH1 in H9c2 cells was reversed by DXZ or FER-1. Therefore, DXZ has protective effects on ferroptosis and cardiomyopathy in rats through regulating HMGB1.
PubMed: 34336950
DOI: 10.3389/fcvm.2021.685434 -
Cureus Jun 2021Multiple myeloma is a pathology of plasma cells, with one of the most common side effects of its treatment is heart failure. In addition, cardiac amyloidosis could cause... (Review)
Review
Multiple myeloma is a pathology of plasma cells, with one of the most common side effects of its treatment is heart failure. In addition, cardiac amyloidosis could cause heart failure by itself. Even though mechanisms of cardiac amyloidosis are known, and they involve lysosomal dysfunction, reactive oxygen species (ROS) accumulation, and infiltrative effect by fibrils, there is no specific agent that could protect from these effects. While the molecular mechanism of doxorubicin cardiotoxicity via topoisomerase II β is established, the only FDA-approved agent for treatment is dexrazoxane. Liposomal doxorubicin can potentially improve response and decrease the development of heart failure due to microscopic liposomes that can accumulate and penetrate only tumor vasculature. Supplements that enhance mitochondrial biogenesis are also shown to improve doxorubicin-induced cardiotoxicity. Other agents, such as JR-311, ICRF-193, and ursolic acid, could potentially become new treatment options. Proteasome inhibitors, novel agents, have significantly improved survival rates among multiple myeloma patients. They act on a proteasome system that is highly active in cardiomyocytes and activates various molecular cascades in malignant cells, as well as in the heart, through nuclear factor kappa B (NF-kB), endoplasmic reticulum (ER), calcineurin-nuclear factor of activated T-cells (NFAT), and adenosine monophosphate-activated protein kinase (AMPKa)/autophagy pathways. Metformin, apremilast, and rutin have shown positive results in animal studies and may become a promising therapy as cardioprotective agents. This article aims to highlight the main molecular mechanisms of heart failure among patients with multiple myeloma and potential treatment options to facilitate the development and research of new preventive strategies. Hence, this will have a positive impact on life expectancy in patients with multiple myeloma.
PubMed: 34336442
DOI: 10.7759/cureus.15943 -
Clinical Science (London, England :... Aug 2021The anthracycline (ANT) anticancer drugs such as doxorubicin or daunorubicin (DAU) can cause serious myocardial injury and chronic cardiac dysfunction in cancer...
The anthracycline (ANT) anticancer drugs such as doxorubicin or daunorubicin (DAU) can cause serious myocardial injury and chronic cardiac dysfunction in cancer survivors. A bisdioxopiperazine agent dexrazoxane (DEX) has been developed as a cardioprotective drug to prevent these adverse events, but it is uncertain whether it is the best representative of the class. The present study used a rabbit model of chronic ANT cardiotoxicity to examine another bisdioxopiperazine compound called GK-667 (meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4,1-diyl))bis(methylene)-bis(2-aminoacetate) hydrochloride), a water-soluble prodrug of ICRF-193 (meso-4,4'-(butan-2,3-diyl)bis(piperazine-2,6-dione)), as a potential cardioprotectant. The cardiotoxicity was induced by DAU (3 mg/kg, intravenously, weekly, 10 weeks), and GK-667 (1 or 5 mg/kg, intravenously) was administered before each DAU dose. The treatment with GK-667 was well tolerated and provided full protection against DAU-induced mortality and left ventricular (LV) dysfunction (determined by echocardiography and LV catheterization). Markers of cardiac damage/dysfunction revealed minor cardiac damage in the group co-treated with GK-667 in the lower dose, whereas almost full protection was achieved with the higher dose. This was associated with similar prevention of DAU-induced dysregulation of redox and calcium homeostasis proteins. GK-667 dose-dependently prevented tumor suppressor p53 (p53)-mediated DNA damage response in the LV myocardium not only in the chronic experiment but also after single DAU administration. These effects appear essential for cardioprotection, presumably because of the topoisomerase IIβ (TOP2B) inhibition provided by its active metabolite ICRF-193. In addition, GK-667 administration did not alter the plasma pharmacokinetics of DAU and its main metabolite daunorubicinol (DAUol) in rabbits in vivo. Hence, GK-667 merits further investigation as a promising drug candidate for cardioprotection against chronic ANT cardiotoxicity.
Topics: Animals; Cardiomyopathies; Cardiotoxicity; Chronic Disease; DNA Damage; Daunorubicin; Diketopiperazines; Disease Models, Animal; Fibrosis; HL-60 Cells; Humans; Male; Myocytes, Cardiac; Prodrugs; Rabbits; Topoisomerase II Inhibitors; Tumor Suppressor Protein p53; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling
PubMed: 34318878
DOI: 10.1042/CS20210311