Chronic anthracycline cardiotoxicity: molecular and functional analysis with focus on nuclear factor erythroid 2-related factor 2 and mitochondrial biogenesis pathways.

Anthracycline anticancer drugs (e.g., doxorubicin or daunorubicin) can induce chronic cardiotoxicity and heart failure (HF), both of which are believed to be based on oxidative injury and mitochondrial damage.

Protective effects of dexrazoxane against acute ischaemia/reperfusion injury of rat hearts.

Dexrazoxane (DEX), an inhibitor of topoisomerase II and intracellular iron chelator, is believed to reduce the formation of reactive oxygen species (ROS) and protects the heart from the toxicity of anthracycline antineoplastics. As ROS also play a role in the pathogenesis of cardiac ischaemia/reperfusion (I/R) injury, the aim was to find out whether DEX can improve cardiac ischaemic tolerance. DEX in a dose of 50, 150, or 450 mg·(kg body mass)(-1) was administered intravenously to rats 60 min before ischaemia.

Daunorubicin does not induce immunohistochemically detectable endothelial dysfunction in rabbit aorta and femoral artery.

Anthracyclines are one of the most effective anticancer drugs ever developed, but their clinical use has been hampered by the risk of severe cardiotoxicity. In this study, we investigated whether rabbits exposed to a different cumulative dose of anthracycline suffer from immunohistochemically detectable vascular toxicity and endothelial dysfunction. Daunorubicin (3 mg/kg, i.

Proteomic insights into chronic anthracycline cardiotoxicity.

Chronic anthracycline cardiotoxicity is a feared complication of cancer chemotherapy. However, despite several decades of primarily hypothesis-driven research, the molecular basis of this phenomenon remains poorly understood. The aim of this study was to obtain integrative molecular insights into chronic anthracycline cardiotoxicity and the resulting heart failure.

In vivo and in vitro assessment of the role of glutathione antioxidant system in anthracycline-induced cardiotoxicity.

The clinical usefulness of anthracycline antineoplastic drugs is limited by their cardiotoxicity. Its mechanisms have not been fully understood, although the induction of oxidative stress is widely believed to play the principal role. Glutathione is the dominant cellular antioxidant, while glutathione peroxidase (GPx) together with glutathione reductase (GR) constitutes the major enzymatic system protecting the cardiac cells from oxidative damage.

Comparison of clinically used and experimental iron chelators for protection against oxidative stress-induced cellular injury.

Iron imbalance plays an important role in oxidative stress associated with numerous pathological conditions. Therefore, iron chelation may be an effective therapeutic approach, but progress in this area is hindered by the lack of effective ligands. Also, the potential favorable effects of chelators against oxidative injury have to be balanced against their own toxicity due to iron depletion and the ability to generate redox-active iron complexes.

Cardiac remodeling and MMPs on the model of chronic daunorubicin-induced cardiomyopathy in rabbits.

The matrix metalloproteinases (MMPs) play a key role during cardiac remodeling. The aim of the study was to investigate the changes in collagenous proteins and MMPs in the model of non-ischemic, anthracycline-induced chronic cardiomyopathy in rabbits using both biochemical and histological approaches. The study was carried out in three groups of Chinchilla male rabbits: 1) daunorubicin (3 mg/kg, once weekly for 10 weeks), 2) control (saline in the same schedule), 3) daunorubicin with the cardioprotectant dexrazoxane (60 mg/kg, before each daunorubicin).

Dexrazoxane-afforded protection against chronic anthracycline cardiotoxicity in vivo: effective rescue of cardiomyocytes from apoptotic cell death.

Background: Dexrazoxane (DEX, ICRF-187) is the only clinically approved cardioprotectant against anthracycline cardiotoxicity. It has been traditionally postulated to undergo hydrolysis to iron-chelating agent ADR-925 and to prevent anthracycline-induced oxidative stress, progressive cardiomyocyte degeneration and subsequent non-programmed cell death. However, the additional capability of DEX to protect cardiomyocytes from apoptosis has remained unsubstantiated under clinically relevant in vivo conditions.

Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron.

The risk of cardiotoxicity is the most serious drawback to the clinical usefulness of anthracycline antineoplastic antibiotics, which include doxorubicin (adriamycin), daunorubicin or epirubicin. Nevertheless, these compounds remain among the most widely used anticancer drugs. The molecular pathogenesis of anthracycline cardiotoxicity remains highly controversial, although the oxidative stress-based hypothesis involving intramyocardial production of reactive oxygen species (ROS) has gained the widest acceptance.

Anthracycline toxicity to cardiomyocytes or cancer cells is differently affected by iron chelation with salicylaldehyde isonicotinoyl hydrazone.

Background And Purpose: The clinical utility of anthracycline antineoplastic drugs is limited by the risk of cardiotoxicity, which has been traditionally attributed to iron-mediated production of reactive oxygen species (ROS).

Experimental Approach: The aims of this study were to examine the strongly lipophilic iron chelator, salicylaldehyde isonicotinoyl hydrazone (SIH), for its ability to protect rat isolated cardiomyocytes against the toxicity of daunorubicin (DAU) and to investigate the effects of SIH on DAU-induced inhibition of proliferation in a leukaemic cell line. Cell toxicity was measured by release of lactate dehydrogenase and staining with Hoechst 33342 or propidium iodide and lipid peroxidation by malonaldehyde formation.

Deferiprone does not protect against chronic anthracycline cardiotoxicity in vivo.

Anthracycline cardiotoxicity ranks among the most severe complications of cancer chemotherapy. Although its pathogenesis is only incompletely understood, "reactive oxygen species (ROS) and iron" hypothesis has gained the widest acceptance. Besides dexrazoxane, novel oral iron chelator deferiprone has been recently reported to afford significant cardioprotection in both in vitro and ex vivo conditions.

Pyridoxal isonicotinoyl hydrazone (PIH) and its analogs as protectants against anthracycline-induced cardiotoxicity.

The risk of cardiotoxicity is the main drawback of anthracycline antibiotics. However, these drugs remain among the most effective and frequently used anti cancer drugs. In this study we aimed to assess the cardioprotective effects of aroylhydrazone iron (FE) chelators: pyridoxal isonicotinoyl hydrazone (PIH) and its two analogs: salicyladehyde isonicotinoyl hydrazone (SIH) and pyridoxal o-chlorbenzoyl hydrazone (o-108).

A pilot study of matrix metalloproteinases on the model of daunorubicin-induced cardiomyopathy in rabbits.

Matrix metalloproteinases (MMPs), activated by oxidative stress, play a key role during cardiac remodeling. In the present study we aimed to assess the role of MMPs in experimental cardiomyopathy induced by repeated 10-week administration of daunorubicin (3 mg/kg i.v.

New iron chelators in anthracycline-induced cardiotoxicity.

The use of anthracycline anticancer drugs is limited by a cumulative, dose-dependent cardiac toxicity. Iron chelation has long been considered as a promising strategy to limit this unfavorable side effect, either by restoring the disturbed cellular iron homeostasis or by removing redox-active iron, which may promote anthracycline-induced oxidative stress. Aroylhydrazone lipophilic iron chelators have shown promising results in the rabbit model of daunorubicin-induced cardiomyopathy as well as in cellular models.

In vitro and in vivo examination of cardiac troponins as biochemical markers of drug-induced cardiotoxicity.

Cardiac troponin T (cTnT) and troponin I (cTnI) are becoming acknowledged as useful biochemical markers of drug-induced cardiotoxicity. In this study we examined the release kinetics of cTnT and cTnI using an in vitro model of isolated rat neonatal ventricular cardiomyocytes (NVCM, 72h treatment with 0.1-3microM of daunorubicin) and compared it with data from a rabbit model of chronic anthracycline-induced cardiomyopathy in vivo (3mg/kg of daunorubicin weekly, 10 weeks).

Evaluation of ECG time intervals in a rabbit model of anthracycline-induced cardiomyopathy: a useful tool for assessment of cardioprotective agents.

The aim of this study was to analyze the ECG time intervals in the course of the development of chronic anthracycline cardiomyopathy in rabbits. Furthermore, this approach was employed to study the effects of a model cardioprotective drug (dexrazoxane) and two novel iron chelating compounds--salicylaldehyde isonicotinoyl hydrazone (SIH) and pyridoxal 2-chlorobenzoyl hydrazone (o-108). Repeated daunorubicin administration induced a significant and progressive prolongation of the QRS complex commencing with the eighth week of administration.

Iron chelation-afforded cardioprotection against chronic anthracycline cardiotoxicity: a study of salicylaldehyde isonicotinoyl hydrazone (SIH).

Pyridoxal-derived aroylhydrazone iron chelators have been previously shown as effective cardioprotectants against chronic anthracycline cardiotoxicity. In this study we focused on a novel salicylaldehyde analogue (salicylaldehyde isonicotinoyl hydrazone, SIH), which has been recently demonstrated to possess marked and dose-dependent protective effects against oxidative injury of cardiomyocytes. Therefore, in the present study the cardioprotective potential of SIH against daunorubicin (DAU) cardiotoxicity was assessed in vitro (isolated rat ventricular cardiomyocytes; DAU 10 microM, 48 h exposure) as well as in vivo (chronic DAU-induced cardiomyopathy in rabbits; DAU 3mg/kg, i.

Early detection of anthracycline cardiotoxicity in a rabbit model: left ventricle filling pattern versus troponin T determination.

Anthracycline cardiotoxicity represents a serious risk of anticancer chemotherapy. The aim of the present pilot study was to compare the potential of both the left ventricular (LV) filling pattern evaluation and cardiac troponin T (cTnT) plasma levels determination for the early detection of daunorubicin-induced cardiotoxicity in rabbits. The echocardiographic measurements of transmitral LV inflow as well as cTnT determinations were performed weekly for 10 weeks in daunorubicin (3 mg/kg weekly) and control groups (n=5, each).

Cardioprotective effects of a novel iron chelator, pyridoxal 2-chlorobenzoyl hydrazone, in the rabbit model of daunorubicin-induced cardiotoxicity.

Iron chelation is the only pharmacological intervention against anthracycline cardiotoxicity whose effectiveness has been well documented both experimentally and clinically. In this study, we aimed to assess whether pyridoxal 2-chlorobenzoyl hydrazone (o-108, a strong iron chelator) can provide effective protection against daunorubicin (DAU)-induced chronic cardiotoxicity in rabbits. First, using the HL-60 leukemic cell line, it was shown that o-108 has no potential to blunt the antiproliferative efficacy of DAU.

HPLC determination of a novel aroylhydrazone iron chelator (o-108) in rabbit plasma and its application to a pilot pharmacokinetic study.

A high performance liquid chromatographic method for the determination of a biocompatible iron chelator, pyridoxal 2-chlorobenzoyl hydrazone (o-108), in rabbit plasma was developed and validated. The separation was achieved on a C18 column with the mobile phase composed of a mixture of 0.01 M phosphate buffer (pH 6) with the addition of EDTA (2 mM), methanol and acetonitrile (42:24:14; v/v/v).

Safety and tolerability of repeated administration of pyridoxal 2-chlorobenzoyl hydrazone in rabbits.

Recently, pyridoxal 2-chlorobenzoyl hydrazone (o-108) has been identified as an effective iron chelator [Link et al., Blood 2003; 101: 4172-79]. Since chronic treatment would be necessary in its potential indications, in the present study, the safety and tolerability of this agent after repeated administration was determined.

Myocardial regulatory proteins and heart failure.

Cardiac troponin T (cTnT) and cardiac troponin I (cTnI) are considered to be the most specific and sensitive biochemical markers of myocardial damage. Troponins have been studied in a wide range of clinical settings, including heart failure; however, there are few data on the role of regulatory proteins in the pathogenesis of heart failure, although a few interesting hypotheses have been proposed. A considerable body of evidence favours the view that alteration of the myocardial thin filament is the primary event leading to defective contractility of the failing myocardium, while the changes in Ca(2+) handling are a compensatory response.

Development of high-performance liquid chromatographic determination of salicylaldehyde isonicotinoyl hydrazone in rabbit plasma and application of this method to an in vivo study.

An analytical methodology appropriate for the determination of the novel drug candidate salicylaldehyde isonicotinoyl hydrazone (SIH) in rabbit plasma has been developed and validated. Desirable chromatographic separation was achieved on a C18 column employing a mixture of phosphate buffer (0.01 M NaH2PO4 x 2 H2O with 2 mM EDTA, pH 6.

Troponin as a marker of myocardiac damage in drug-induced cardiotoxicity.

Cardiac troponins T and I (cTnT and cTnI) are becoming the serum biomarkers of choice for monitoring potential drug-induced myocardial injury in both clinical and preclinical studies. The utility of cardiac troponins has been mainly demonstrated following the administration of antineoplastic drugs and beta-sympathomimetics, although the routine use of these markers in the monitoring in patients who received anthracyclines therapy is far from settled. Unlike the previous markers, which suffered from numerous shortages, the main advantages of cardiac troponins are their high specificity and sensitivity, wide diagnostic window and the possibility to use commercially available assays in clinical settings as well as in a broad range of laboratory animals.