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Interventions for preventing cardiomyopathy due to anthracyclines: a Bayesian network meta-analysis.Annals of Oncology : Official Journal... Mar 2017The relative efficacy of interventions for primary prevention of anthracycline-associated cardiotoxicity is unknown. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The relative efficacy of interventions for primary prevention of anthracycline-associated cardiotoxicity is unknown.
METHODS
We conducted a systematic review of randomized controlled trials for primary prevention of anthracycline-associated cardiotoxicity in adult cancer patients. We used hierarchal outcome definitions in the following order of priority: (1) composite of heart failure or decline in left ventricular ejection fraction, (2) decline in ejection fraction, or (3) heart failure. Data were analyzed using a Bayesian network meta-analysis with random effects.
RESULTS
A total of 16 trials reported cardiotoxicity as a dichotomous outcome among 1918 patients, evaluating dexrazoxane, angiotensin antagonists, beta-blockers, combination angiotensin antagonists and beta-blockers, statins, Co-enzyme Q-10, prenylamine, and N-acetylcysteine. Compared with control, dexrazoxane reduced cardiotoxicity with a pooled odds ratio (OR) of 0.26 (95% credible interval [CrI] 0.11-0.74) and had the highest probability (33%) of being most effective. No other agent was demonstrably better than placebo. Angiotensin antagonists had an 84% probability of being most effective in a sensitivity analysis excluding one outlying study (OR 0.06 [95% CrI 0.01- 0.24]). When the outcome was restricted to heart failure, dexrazoxane was associated with an OR of 0.12 (95% CrI 0.06-0.23) relative to control and had 58% probability of being most effective, while angiotensin antagonists had an OR of 0.18 (95% CrI 0.05-0.55). Available data suggested that dexrazoxane and angiotensin antagonists did not affect malignancy response rate or risk of death.
CONCLUSION
Moderate quality data suggest that dexrazoxane, and low quality data suggest angiotensin antagonists, are likely to be effective for cardiotoxicity prevention.
Topics: Acetylcysteine; Adrenergic beta-Antagonists; Angiotensins; Anthracyclines; Cardiomyopathies; Clinical Trials as Topic; Dexrazoxane; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Neoplasms; Network Meta-Analysis; Prenylamine; Ventricular Dysfunction, Left
PubMed: 28028033
DOI: 10.1093/annonc/mdw671 -
Journal of Rare Diseases Research &... 2016Pulmonary arterial hypertension (PAH) is rare, but patients who are diagnosed with this disease still suffer from a lack of satisfactory treatment strategies to prolong...
Pulmonary arterial hypertension (PAH) is rare, but patients who are diagnosed with this disease still suffer from a lack of satisfactory treatment strategies to prolong survival. While currently approved drugs for PAH have some benefits, these vasodilators only have limited efficacy for eliminating pulmonary vascular remodeling and reducing mortality. Thus, our laboratory has been exploring the use of aggressive drugs, which are capable of causing apoptotic cell death, to treat PAH. We have so far found that three classes of anti-tumor agents, including anthracyclines, taxanes, and proteasome inhibitors, are capable of reducing pulmonary vascular thickness in rats with PAH. These drugs kill cells in remodeled pulmonary vessels without affecting the normal, healthy pulmonary vasculature, revealing that proliferating vascular cells in PAH patients are more sensitive to drug-induced apoptosis compared to the differentiated phenotype that is physiologically important for smooth muscle contraction. Since many apoptosis-inducing drugs cause cardiotoxicity in cancer patients, and because PAH patients already have a weakened heart, we focus on finding biological mechanisms that may reverse pulmonary vascular remodeling without promoting cardiotoxicity. We found two agents, dexrazoxane and pifithrin-α, that selectively inhibit cardiac muscle apoptosis without affecting the drug-induced apoptosis of the proliferating pulmonary vascular cells. Thus, we propose that the addition of apoptosis-inducing drugs and cardioprotectants to PAH therapies may be effective in treating patients and preventing right heart failure.
PubMed: 27819072
DOI: No ID Found -
Pharmaceutical Biology Dec 2022Shengmai injection (SMI) has been used to treat heart failure.
CONTEXT
Shengmai injection (SMI) has been used to treat heart failure.
OBJECTIVE
This study determines the molecular mechanisms of SMI against cardiotoxicity caused by doxorubicin (DOX).
MATERIALS AND METHODS
, DOX (15 mg/kg) was intraperitoneally injected in model, Dex (dexrazoxane), SMI-L (2.7 mL/kg), SMI-M (5.4 mL/kg), and SMI-H (10.8 mL/kg) for 7 consecutive days. Hematoxylin-eosin (HE) and Masson staining were used to evaluate histological changes, and cardiomyocyte apoptosis was identified using TdT-mediated dUTP nick-end labelling (TUNEL). Enzymatic indexes were determined. mRNA and protein expressions were analysed through RT-qPCR and Western blotting. , H9c2 cells were divided into control group, model group (2 mL 1 μM DOX), SMI group, ML385 group, and SMI + ML385 group, the intervention lasted for 24 h. mRNA and protein expressions were analysed.
RESULTS
SMI markedly improved cardiac pathology, decreased cardiomyocyte apoptosis, increased creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA), decreased superoxide dismutase (SOD). Compared with the model group, the protein expression of nuclear factor erythroid2-related factor 2 (Nrf2) (SMI-L: 2.42-fold, SMI-M: 2.67-fold, SMI-H: 3.07-fold) and haem oxygenase-1(HO-1) (SMI-L: 1.64-fold, SMI-M: 2.01-fold, SMI-H: 2.19-fold) was increased and the protein expression of kelch-like ECH-associated protein 1 (Keap1) (SMI-L: 0.90-fold, SMI-M: 0.77-fold, SMI-H: 0.66-fold) was decreased in SMI groups and Dex group . Additionally, SMI dramatically inhibited apoptosis, decreased CK, LDH and MDA levels, and enhanced SOD activity. Our results demonstrated that SMI reduced DOX-induced cardiotoxicity via activation of the Nrf2/Keap1 signalling pathway.
CONCLUSIONS
This study revealed a new mechanism by which SMI alleviates DOX-induced 45 cardiomyopathy by modulating the Nrf2/Keap1 signal pathway.
Topics: Animals; Apoptosis; Cardiotoxicity; Cells, Cultured; Doxorubicin; Drug Combinations; Drugs, Chinese Herbal; Kelch-Like ECH-Associated Protein 1; Molecular Docking Simulation; Myocardium; NF-E2-Related Factor 2; Rats; Rats, Sprague-Dawley; Signal Transduction
PubMed: 35298357
DOI: 10.1080/13880209.2022.2046801 -
Cardio-oncology (London, England) Jun 2021Cancer therapy-related cardiac dysfunction may occur in pediatric cancer survivors. Identification of early markers of myocardial damage secondary to anthracycline...
BACKGROUND
Cancer therapy-related cardiac dysfunction may occur in pediatric cancer survivors. Identification of early markers of myocardial damage secondary to anthracycline exposure is crucial to develop strategies that may ameliorate this complication.
OBJECTIVES
The purpose of this study was to identify early myocardial changes induced by doxorubicin with and without cardioprotection using dexrazoxane detected by serial cardiac magnetic resonance imaging (CMR) in a pre-clinical mouse model.
METHODS
Serial CMR examinations were performed in 90 mice distributed in 3 groups: 45 received doxorubicin (DOX group), 30 mice received doxorubicin with dexrazoxane (DOX/DEX group) and 15 mice received saline injections (control group). We obtained the following CMR parameters in all mice: T2, extracellular volume quantification (ECV), myocardial deformation, and functional quantification.
RESULTS
Myocardial edema assessed by T2 time was the earliest parameter demonstrating evidence of myocardial injury, most notable in the DOX group at week 4 and 8 compared with DOX/DEX group. Similarly, global longitudinal strain was abnormal in both the DOX and DOX/DEX groups. However, this change persisted only in the DOX group. The ECV was significantly elevated in the DOX group at the final CMR, while only minimally elevated in the DOX/DEX group. The right and left ejection fraction was decreased, along with the mass to volume ratio in the DOX group. The T2 time, ECV, and deformation correlated with ejection fraction and left ventricular volume.
CONCLUSIONS
T2 time and deformation by CMR identifies early myocardial injury from anthracyclines. Dexrazoxne did not prevent the initial edema, but the inflammatory changes were not sustained. CMR may be useful for early detection of cardiac dysfunction. Serial CMR demonstrates dexrazoxane minimizes cardiac dysfunction and aids recovery in a mouse model.
PubMed: 34134789
DOI: 10.1186/s40959-021-00109-8 -
American Journal of Physiology. Heart... Sep 2018The chemotherapeutic effect of doxorubicin (Dox) is limited by cumulative dose-dependent cardiotoxicity in cancer survivors. Dexrazoxane (DRZ) is approved to prevent...
The chemotherapeutic effect of doxorubicin (Dox) is limited by cumulative dose-dependent cardiotoxicity in cancer survivors. Dexrazoxane (DRZ) is approved to prevent Dox-induced cardiotoxicity. Humanin and its synthetic analog HNG have a cytoprotective effect on the heart. To investigate the cardioprotective efficacy of HNG alone or in combination with DRZ against Dox-induced cardiotoxicity, 80 adult male mice were randomly divided into 8 groups to receive the following treatments via intraperitoneal injection: saline dailym HNG (5 mg/kg) daily, DRZ (60 mg/kg) weekly, Dox (3 mg/kg) weekly, DRZ + HNG, Dox + HNG, Dox + DRZ, and Dox + HNG + DRZ. Echocardiograms were performed before and at 4, 8, and 9.5 wk after the beginning of treatment. All mice were euthanized at 10 wk. In the absence of Dox, HNG, DRZ, or DRZ + HNG had no adverse effect on the heart. Dox treatment caused decreases in ejection fraction and cardiac mass and increases in cardiomyocyte apoptosis and intracardiac fibrosis. HNG or DRZ alone blunted the Dox-induced decrease in left ventricle posterior wall thickness and modestly ameliorated the Dox-induced decrease in ejection fraction. HNG + DRZ significantly ameliorated Dox-induced decreases in ejection function, cardiac fibrosis, and cardiac mass. Using a targeted analysis for the mitochondrial gene array and protein expression in heart tissues, we demonstrated that HNG + DRZ reversed DOX-induced altered transcripts that were biomarkers of cardiac damage and uncoupling protein-2. We conclude that HNG enhances the cardiac protective effect of DRZ against Dox-induced cardiotoxicity. HNG + DRZ protects mitochondria from Dox-induced cardiac damage and blunts the onset of cardiac dysfunction. Thus, HNG may be an adjuvant to DRZ in preventing Dox-induced cardiotoxicity. NEW & NOTEWORTHY Doxorubicin (Dox) is commonly used for treating a wide range of human cancers. However, cumulative dosage-dependent carditoxicity often limits its clinical applications. We demonstrated in this study that treating young adult male mice with synthetic humanin analog enhanced the cardiac protective effect of dexrazoxane against chemotherapeutic agent Dox-induced cardiac dysfunction. Thus, humanin analog can potentially serve as an adjuvant to dexrazoxane in more effectively preventing Dox-induced cardiac dysfunction and cardiomyopathy.
Topics: Animals; Cardiotonic Agents; Cardiotoxicity; Dexrazoxane; Doxorubicin; Drug Synergism; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac
PubMed: 29775411
DOI: 10.1152/ajpheart.00155.2018 -
British Journal of Cancer Jan 2007This review systematically assessed the evidence on the clinical and cost-effectiveness of cardioprotection against the toxic effects of anthracyclines given to children... (Review)
Review
This review systematically assessed the evidence on the clinical and cost-effectiveness of cardioprotection against the toxic effects of anthracyclines given to children with cancer. We searched eight electronic databases, including Medline and the Cochrane Library, from inception to January 2006 for systematic reviews and randomised controlled trials that reported death, heart failure, arrhythmias or measures of cardiac performance associated with cardioprotective technologies compared with standard treatment in children treated for cancer with anthracyclines. Economic evaluations were also sought. Inclusion criteria, data extraction and quality assessment were undertaken by standard methodology. Four randomised controlled trials met the inclusion criteria of the review; each had methodological limitations. No economic evaluations were identified. Studies were combined through narrative synthesis. One trial found that continuous infusion of doxorubicin did not offer any cardioprotection over rapid infusion. One suggested that continuous infusion of daunorubicin provoked less cardiotoxicity than rapid infusion. One concluded that dexrazoxane reduces cardiac injury during doxorubicin therapy and one reported a protective effect of coenzyme Q(10) on cardiac function during anthracycline therapy. The evidence on the effectiveness of cardioprotective technologies in children is limited in quality and quantity thus making conclusions difficult. This is surprising given the importance of anthracycline use in children with cancer. Further long-term research, which includes relevant outcome measures, is needed to determine whether technologies influence the development of cardiac damage without limiting the antitumour efficacy of anthracyclines.
Topics: Anthracyclines; Cardiotonic Agents; Child; Humans; State Medicine
PubMed: 17242696
DOI: 10.1038/sj.bjc.6603562 -
BMJ (Clinical Research Ed.) Oct 1999
Topics: Antibiotics, Antineoplastic; Chelating Agents; Heart; Humans; Razoxane
PubMed: 10531081
DOI: 10.1136/bmj.319.7217.1085 -
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 -
Biomedicine & Pharmacotherapy =... Aug 2021Cancer is one of the leading causes of deaths worldwide with 18.1 million deaths per year. Although there have been significant advances in anti-cancer therapies, they... (Comparative Study)
Comparative Study
Cancer is one of the leading causes of deaths worldwide with 18.1 million deaths per year. Although there have been significant advances in anti-cancer therapies, they can often result in side effects with cardiovascular complications being the most severe. Dexrazoxane is the only currently approved treatment for prevention of anthracycline induced cardiotoxicity but there are concerns about its use due to the development of secondary malignancies and myelodysplastic syndrome. Additionally, it is only recommended in patients who are due to receive a total cumulative dose of 300 mg/m of doxorubicin or 540 mg/m of epirubicin. Thus, there exists an urgent need to develop new therapeutic strategies to counteract anthracycline induced cardiotoxicity. The h9c2 cardiomyoblast was investigated for its differentiation capacity and used to screen and compare promising prophylactics for doxorubicin induced cardiotoxicity. The half maximal inhibitory concentration of doxorubicin was determined in differentiated h9c2 cells after 24 h of exposure, to establish a model for drug screening. Cells were treated with dexrazoxane, resveratrol, and carvedilol either 3 h or 24 h prior to doxorubicin treatment. The ability of these cardioprotectants to prevent cardiotoxicity was analysed using the cck-8 cell viability assay and the dichlorofluorescin diacetate (DCFDA) reactive oxygen species (ROS) assay. There was no significant increase in survival in treatment groups after 3 h, however, at 24 h, resveratrol significantly improved survival compared to all other groups (p < 0.05). Additionally, dexrazoxane and resveratrol significantly decreased ROS formation at 3 h (p < 0.05) and all groups significantly decreased ROS production at 24 h (p < 0.001). This work is the first comparison of these cardioprotectants and suggests that resveratrol may be a more effective treatment in the prevention of anthracycline induced cardiotoxicity, compared to dexrazoxane and carvedilol. However, further work will be needed in order to decipher the exact mechanism and potential of this drug in the clinic.
Topics: Animals; Antibiotics, Antineoplastic; Cardiotonic Agents; Cardiotoxicity; Carvedilol; Cell Line; Cell Survival; Dexrazoxane; Doxorubicin; Rats; Reactive Oxygen Species; Resveratrol
PubMed: 34015579
DOI: 10.1016/j.biopha.2021.111702 -
Hematology. American Society of... Dec 2021Anthracycline chemotherapy remains an integral component of modern pediatric acute myeloid leukemia (AML) regimens and is often delivered at high doses to maximize...
Anthracycline chemotherapy remains an integral component of modern pediatric acute myeloid leukemia (AML) regimens and is often delivered at high doses to maximize cancer survival. Unfortunately, high-dose anthracyclines are associated with a significant risk of cardiotoxicity, which may result in early and/or long-term left ventricular systolic dysfunction and heart failure. Moreover, the development of cardiotoxicity during pediatric AML therapy is associated with lower event-free and overall survival, which may be partially attributable to incomplete anthracycline delivery. A combined strategy of primary cardioprotection and close cardiac monitoring can maximize chemotherapy delivery while reducing the toxicity of intensive AML therapy. Primary cardioprotection using dexrazoxane reduces short-term cardiotoxicity without compromising cancer survival. Liposomal anthracycline formulations, which are under active investigation, have the potential to mitigate cardiotoxicity while also improving antitumor efficacy. Primary cardioprotective strategies may reduce but not eliminate the risk of cardiotoxicity; therefore, close cardiac monitoring is also needed. Standard cardiac monitoring consists of serial echocardiographic assessments for left ventricular ejection fraction decline. Global longitudinal strain has prognostic utility in cancer therapy-related cardiotoxicity and may be used as an adjunct assessment. Additional cardioprotective measures should be considered in response to significant cardiotoxicity; these include cardiac remodeling medications to support cardiac recovery and anthracycline dose interruption and/or regimen modifications. However, the withholding of anthracyclines should be limited to avoid compromising cancer survival. A careful approach to cardioprotection during AML therapy is critical to maximize the efficacy of leukemia treatment while minimizing the short- and long-term risks of cardiotoxicity.
Topics: Adolescent; Anthracyclines; Antineoplastic Agents; Cardiotonic Agents; Cardiotoxicity; Child; Dexrazoxane; Female; Heart; Humans; Leukemia, Myeloid, Acute
PubMed: 34889355
DOI: 10.1182/hematology.2021000268