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; P<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; P<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.
- MeSH
- Anthracyclines adverse effects pharmacology MeSH
- Daunorubicin metabolism pharmacology MeSH
- Dexrazoxane adverse effects pharmacology MeSH
- DNA Topoisomerases, Type II adverse effects metabolism MeSH
- Topoisomerase II Inhibitors metabolism MeSH
- Myocytes, Cardiac drug effects metabolism MeSH
- Cardiotoxicity drug therapy metabolism prevention & control MeSH
- Humans MeSH
- Heart Diseases drug therapy MeSH
- Oxidative Stress drug effects MeSH
- Antibiotics, Antineoplastic adverse effects pharmacology MeSH
- Heart Failure drug therapy MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical practice against anthracycline cardiotoxicity. However, the poor aqueous solubility of ICRF-193 has precluded its further in vivo development as a cardioprotective agent. To overcome this issue, water-soluble prodrugs of ICRF-193 were prepared, their abilities to release ICRF-193 were investigated using a novel UHPLC-MS/MS assay, and their cytoprotective effects against anthracycline cardiotoxicity were tested in vitro in neonatal ventricular cardiomyocytes (NVCMs). Based on the obtained results, the bis(2-aminoacetoxymethyl)-type prodrug GK-667 was selected for advanced investigations due to its straightforward synthesis, sufficient solubility, low cytotoxicity and favorable ICRF-193 release. Upon administration of GK-667 to NVCMs, the released ICRF-193 penetrated well into the cells, reached sufficient intracellular concentrations and provided effective cytoprotection against anthracycline toxicity. The pharmacokinetics of the prodrug, ICRF-193 and its rings-opened metabolite was estimated in vivo after administration of GK-667 to rabbits. The plasma concentrations of ICRF-193 reached were found to be adequate to achieve cardioprotective effects in vivo. Hence, GK-667 was demonstrated to be a pharmaceutically acceptable prodrug of ICRF-193 and a promising drug candidate for further evaluation as a potential cardioprotectant against chronic anthracycline toxicity.
- MeSH
- Anthracyclines adverse effects MeSH
- Dexrazoxane chemistry pharmacology MeSH
- Diketopiperazines chemistry pharmacology MeSH
- DNA Topoisomerases, Type II metabolism MeSH
- Topoisomerase II Inhibitors chemistry pharmacology MeSH
- Myocytes, Cardiac drug effects metabolism MeSH
- Cardiotonic Agents chemistry pharmacology MeSH
- Cardiotoxicity drug therapy metabolism MeSH
- Rabbits MeSH
- Piperazine chemistry pharmacology MeSH
- Prodrugs chemistry pharmacology MeSH
- Razoxane chemistry pharmacology MeSH
- Water chemistry MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Bisdioxopiperazine agent dexrazoxane (ICRF-187) has been the only effective and approved drug for prevention of chronic anthracycline cardiotoxicity. However, the structure-activity relationships (SARs) of its cardioprotective effects remain obscure owing to limited investigation of its derivatives/analogs and uncertainties about its mechanism of action. To fill these knowledge gaps, we tested the hypothesis that dexrazoxane derivatives exert cardioprotection via metal chelation and/or modulation of topoisomerase IIβ (Top2B) activity in chronic anthracycline cardiotoxicity. Dexrazoxane was alkylated in positions that should not interfere with the metal-chelating mechanism of cardioprotective action; that is, on dioxopiperazine imides or directly on the dioxopiperazine ring. The protective effects of these agents were assessed in vitro in neonatal cardiomyocytes. All studied modifications of dexrazoxane molecule, including simple methylation, were found to abolish the cardioprotective effects. Because this challenged the prevailing mechanistic concept and previously reported data, the two closest derivatives [(±)-4,4'-(propane-1,2-diyl)bis(1-methylpiperazine-2,6-dione) and 4-(2-(3,5-dioxopiperazin-1-yl)ethyl)-3-methylpiperazine-2,6-dione] were thoroughly scrutinized in vivo using a rabbit model of chronic anthracycline cardiotoxicity. In contrast to dexrazoxane, both compounds failed to protect the heart, as demonstrated by mortality, cardiac dysfunction, and myocardial damage parameters, although the pharmacokinetics and metal-chelating properties of their metabolites were comparable to those of dexrazoxane. The loss of cardiac protection was shown to correlate with their abated potential to inhibit and deplete Top2B both in vitro and in vivo. These findings suggest a very tight SAR between bisdioxopiperazine derivatives and their cardioprotective effects and support Top2B as a pivotal upstream druggable target for effective cardioprotection against anthracycline cardiotoxicity. SIGNIFICANCE STATEMENT: This study has revealed the previously unexpected tight structure-activity relationships of cardioprotective effects in derivatives of dexrazoxane, which is the only drug approved for the prevention of cardiomyopathy and heart failure induced by anthracycline anticancer drugs. The data presented in this study also strongly argue against the importance of metal-chelating mechanisms for the induction of this effect and support the viability of topoisomerase IIβ as an upstream druggable target for effective and clinically translatable cardioprotection.
- MeSH
- Anthracyclines adverse effects MeSH
- Dexrazoxane pharmacology MeSH
- DNA Topoisomerases, Type II metabolism MeSH
- HL-60 Cells MeSH
- Topoisomerase II Inhibitors pharmacology MeSH
- Myocytes, Cardiac drug effects metabolism MeSH
- Cardiomyopathies drug therapy metabolism MeSH
- Cardiotoxicity drug therapy MeSH
- Rabbits MeSH
- Rats MeSH
- Humans MeSH
- Models, Animal MeSH
- Myocardium metabolism MeSH
- Cell Line, Tumor MeSH
- Protective Agents pharmacology MeSH
- Rats, Wistar MeSH
- Heart drug effects MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Rats MeSH
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Dexrazoxane (DEX), the only cardioprotectant approved against anthracycline cardiotoxicity, has been traditionally deemed to be a prodrug of the iron-chelating metabolite ADR-925. However, pharmacokinetic profile of both agents, particularly with respect to the cells and tissues essential for its action (cardiomyocytes/myocardium), remains poorly understood. The aim of this study is to characterize the conversion and disposition of DEX to ADR-925 in vitro (primary cardiomyocytes) and in vivo (rabbits) under conditions where DEX is clearly cardioprotective against anthracycline cardiotoxicity. Our results show that DEX is hydrolyzed to ADR-925 in cell media independently of the presence of cardiomyocytes or their lysate. Furthermore, ADR-925 directly penetrates into the cells with contribution of active transport, and detectable concentrations occur earlier than after DEX incubation. In rabbits, ADR-925 was detected rapidly in plasma after DEX administration to form sustained concentrations thereafter. ADR-925 was not markedly retained in the myocardium, and its relative exposure was 5.7-fold lower than for DEX. Unlike liver tissue, myocardium homogenates did not accelerate the conversion of DEX to ADR-925 in vitro, suggesting that myocardial concentrations in vivo may originate from its distribution from the central compartment. The pharmacokinetic parameters for both DEX and ADR-925 were determined by both noncompartmental analyses and population pharmacokinetics (including joint parent-metabolite model). Importantly, all determined parameters were closer to human than to rodent data. The present results open venues for the direct assessment of the cardioprotective effects of ADR-925 in vitro and in vivo to establish whether DEX is a drug or prodrug.
- MeSH
- Dexrazoxane blood metabolism pharmacokinetics urine MeSH
- Ethylenediamines metabolism pharmacokinetics MeSH
- Glycine analogs & derivatives metabolism pharmacokinetics MeSH
- Myocytes, Cardiac metabolism MeSH
- Cardiotonic Agents blood metabolism pharmacokinetics pharmacology MeSH
- Rabbits MeSH
- Rats MeSH
- Tissue Distribution MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Novel dexrazoxane derivative JR-311 was prepared to investigate structure-activity relationships and mechanism(s) of protection against anthracycline cardiotoxicity. Its cardioprotective, antiproliferative, iron (Fe) chelation and inhibitory and/or depletory activities on topoisomerase IIbeta (TOP2B) were examined and compared with dexrazoxane. While in standard assay, JR-311 failed in both cardioprotection and depletion of TOP2B, its repeated administration to cell culture media led to depletion of TOP2B and significant protection of isolated rat neonatal ventricular cardiomyocytes from daunorubicin-induced damage. This effect was explained by a focused analytical investigation that revealed rapid JR-311 decomposition, resulting in negligible intracellular concentrations of the parent compound but high exposure of cells to the decomposition products, including Fe-chelating JR-H2. Although chemical instability is an obstacle for the development of JR-311, this study identified a novel dexrazoxane analogue with preserved pharmacodynamic properties, contributed to the investigation of structure-activity relationships and suggested that the cardioprotection of bis-dioxopiperazines is likely attributed to TOP2B activity of the parent compound rather than Fe chelation of their hydrolytic metabolites/degradation products. Moreover, this study highlights the importance of early stability testing during future development of novel dexrazoxane analogues.
- MeSH
- Anthracyclines toxicity MeSH
- Iron Chelating Agents pharmacology MeSH
- Daunorubicin toxicity MeSH
- Dexrazoxane analogs & derivatives pharmacology MeSH
- Diketopiperazines pharmacology MeSH
- DNA Topoisomerases, Type II metabolism MeSH
- Myocytes, Cardiac drug effects MeSH
- Cardiotonic Agents pharmacology MeSH
- Cardiotoxicity drug therapy etiology MeSH
- Rats MeSH
- Cells, Cultured MeSH
- Animals, Newborn MeSH
- Rats, Wistar MeSH
- Cell Proliferation drug effects MeSH
- Structure-Activity Relationship MeSH
- Iron metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Dexrazoxane (DEX) is a clinically available cardioprotectant that reduces the toxicity induced by anthracycline (ANT) anticancer drugs; however, DEX is seldom used and its action is poorly understood. Inorganic nitrate/nitrite has shown promising results in myocardial ischemia-reperfusion injury and recently in acute high-dose ANT cardiotoxicity. However, the utility of this approach for overcoming clinically more relevant chronic forms of cardiotoxicity remains elusive. Hence, in this study, the protective potential of inorganic nitrate and nitrite against chronic ANT cardiotoxicity was investigated, and the results were compared to those using DEX. Chronic cardiotoxicity was induced in rabbits with daunorubicin (DAU). Sodium nitrate (1g/L) was administered daily in drinking water, while sodium nitrite (0.15 or 5mg/kg) or DEX (60mg/kg) was administered parenterally before each DAU dose. Although oral nitrate induced a marked increase in plasma NOx, it showed no improvement in DAU-induced mortality, myocardial damage or heart failure. Instead, the higher nitrite dose reduced the incidence of end-stage cardiotoxicity, prevented related premature deaths and significantly ameliorated several molecular and cellular perturbations induced by DAU, particularly those concerning mitochondria. The latter result was also confirmed in vitro. Nevertheless, inorganic nitrite failed to prevent DAU-induced cardiac dysfunction and molecular remodeling in vivo and failed to overcome the cytotoxicity of DAU to cardiomyocytes in vitro. In contrast, DEX completely prevented all of the investigated molecular, cellular and functional perturbations that were induced by DAU. Our data suggest that the difference in cardioprotective efficacy between DEX and inorganic nitrite may be related to their different abilities to address a recently proposed upstream target for ANT in the heart - topoisomerase IIβ.
- MeSH
- Daunorubicin adverse effects MeSH
- Dexrazoxane pharmacology MeSH
- DNA-Binding Proteins antagonists & inhibitors metabolism MeSH
- DNA Topoisomerases, Type II metabolism MeSH
- Nitrates pharmacology MeSH
- Sodium Nitrite pharmacology MeSH
- Infusions, Intravenous MeSH
- Myocytes, Cardiac metabolism pathology MeSH
- Cardiotonic Agents pharmacology MeSH
- Cardiotoxicity metabolism pathology prevention & control MeSH
- Rabbits MeSH
- Myocardium metabolism pathology MeSH
- Antibiotics, Antineoplastic adverse effects MeSH
- Drug Administration Schedule MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
The newly developed interface-free capillary electrophoresis-nanospray/mass spectrometry system (CE-nESI/MS) was applied for rapid analysis of the cardioprotective drug dexrazoxane and its hydrolysed form ADR-925 in deproteinized blood plasma samples. The aim of this study was to test the simplest possible CE-nESI/MS instrumentation for analyses of real samples. This interface-free system, utilizing single piece of a narrow bore capillary as both the electrophoretic separation column and the nanospray emitter, was operated at a flow rate of 30nL/min. Excellent electrophoretic separation and sensitive nanospray ionization was achieved with the use of only one high voltage power supply. In addition, hydrophobic external coating was developed and tested for additional stability of the nanospray ionization. To our knowledge this is the first study devoted to the analysis of dexrazoxane and ADR-925 by capillary electrophoresis-mass spectrometry.
Antracykliny můžeme charakterizovat jako velice významná protinádorová antibiotika s širokým spektrem využití při léčbě solidních nádorů a hematologických onemocnění. Ačkoliv jsou antracykliny účinnými cytostatiky, jsme při léčbě omezeni jejich kardiotoxickými účinky. V tomto přehledovém článku se zabýváme mechanizmem účinku léčiva, vznikem kardiotoxicity a jejími klinickými projevy. Dále se budeme věnovat kardioprotekci, s jejíž pomocí se snažíme eliminovat poškození srdečního svalu následkem léčby.
We can characterize anthracyclines as very important anti-tumour antibiotics with wide range of use in therapy of solid tumours and haematological diseases. Although anthracyclines are efficient in treatment of cancer, their use is quite limited by their cardiotoxic effects. In this review we are focusing on the mechanism of function of the drug, the origin of cardiotoxicity and its clinical manifestation. Then we will be talking about cardioprotection which could eliminate the damage of the heart muscle by the treatment.
- Keywords
- kardioprotektivní látky,
- MeSH
- Anthracyclines * administration & dosage adverse effects therapeutic use MeSH
- Dexrazoxane administration & dosage adverse effects therapeutic use MeSH
- Doxorubicin * administration & dosage adverse effects therapeutic use MeSH
- Financing, Organized MeSH
- Cardiotoxicity etiology complications prevention & control MeSH
- Dietary Supplements MeSH
- Antineoplastic Agents * administration & dosage adverse effects therapeutic use MeSH
- Risk Factors MeSH
- Age Factors MeSH
- Vitamins MeSH
- Check Tag
- Female MeSH
Extravazace představuje situaci, kdy dojde k úniku léčiva (určeného primárně k nitrožilní aplikaci) mimo cévní systém do okolních tkání. Dochází k poškození okolních struktur různé intenzity dle charakteru extravazátu a jeho objemu. Nejhorší bývají následky v případě extravazace některých cytostatik. V článku jsou shrnuty druhy rizikových cytostatik, možnosti prevence a opatření, která je nutno provést v případě, že k takové epizodě dojde. Máme k dispozici i několik specifických antidot, která však nejsou ve všech zemích dostupná, a opodstatnění pro jejich podání je navíc podloženo vědeckými články různé hladiny významnosti. Shrnujeme aktuální mezinárodní doporučení pro postup v případě extravazace.
Extravasation is the leakage of a drug (intended primarily for intravenous administration) into tissues surrounding the vascular system. The damage to surrounding varies depending on the nature and volume of extravasation. Cytostatic extravasation is associated with poor outcomes for patients. This paper summarizes the types of risk associated with cytostatic extravasation, and the preventative measures that can be used when such an event occurs. We also provide information on potential treatments. However, justification for their use has only been substantiated in papers with different levels of significance and these papers are not available in all countries. We summarize current international recommendations for actions to be taken in the event of extravasation. Key words: extravasation – cytostatic agents – soft tissues injuries – antidotes – catheterization The author declares he has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 23. 6. 2015 Accepted: 9. 1. 2016
- MeSH
- Antidotes * therapeutic use MeSH
- Risk Reduction Behavior MeSH
- Cytostatic Agents * classification adverse effects MeSH
- Debridement MeSH
- Dexrazoxane therapeutic use MeSH
- Dimethyl Sulfoxide therapeutic use MeSH
- Extravasation of Diagnostic and Therapeutic Materials * diagnosis prevention & control therapy MeSH
- Adrenal Cortex Hormones adverse effects MeSH
- Hyaluronoglucosaminidase therapeutic use MeSH
- Infusions, Intravenous adverse effects MeSH
- Catheterization, Central Venous adverse effects MeSH
- Catheterization adverse effects MeSH
- Skin Diseases chemically induced therapy MeSH
- Therapeutic Irrigation MeSH
- Humans MeSH
- Necrosis chemically induced therapy MeSH
- Catheterization, Peripheral adverse effects MeSH
- Soft Tissue Injuries chemically induced therapy MeSH
- Risk Factors MeSH
- Ulcer chemically induced therapy MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
The purpose of the present study was to compare the activity of two different clinically available iron chelators on the development of acute liver injury after administration of the bacterial endotoxin (lipopolysaccharide [LPS]) in rats. Lipopolysaccharide was administered either alone or after pretreatment with dexrazoxane (DEX) or deferoxamine (DFO). Control groups received only saline or its combination with either chelator. After 8 h, untreated LPS rats developed liver injury, with signs of inflammation and oxidative stress. Lipopolysaccharide reduced plasma iron concentrations in association with increased production of hepcidin and the reduced liver expression of ferroportin. Administration of chelating agents to LPS animals showed distinct effects. Although both drugs were able to reduce liver iron content, together with corresponding changes in hepcidin and ferroportin expressions, only DFO showed a protective effect against liver injury despite relatively small liver concentrations. In sharp contrast, DEX failed to improve any hallmark of liver injury and even worsened the GSH/GSSG ratio, the indicator of oxidative stress in the tissue. High-performance liquid chromatography-mass spectrometry analysis showed marked liver accumulation of iron-chelating metabolite of DEX (ADR-925), whereas the parent compound was undetectable. Further downregulation of transporters involved in bile formation was observed after DFO in the LPS group as well as in healthy animals. Neither chelator imposed significant liver injury in healthy animals. In conclusion, we demonstrated marked differences in the modulation of endotoxemic liver impairment between two iron chelators, implicating that particular qualities of chelating agents may be of crucial importance.
- MeSH
- Iron Chelating Agents therapeutic use MeSH
- Deferoxamine therapeutic use MeSH
- Dexrazoxane therapeutic use MeSH
- Endotoxemia complications MeSH
- Rats MeSH
- Liver Diseases drug therapy etiology MeSH
- Rats, Wistar MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
