Background: Cardiac toxicity associated with chronic administration of anthracycline (ANT) antibiotics represents a serious complication of their use in anticancer chemotherapy, but can also serve as a useful experimental model of cardiomyopathy and congestive heart failure. Aims: In this study, a model of chronic ANT cardiotoxicity induced by repeated i.v. daunorubicin (DAU) administration to rabbits was tested. Methods: Three groups of animals were used: (1) control group-10 animals received i.v. saline; (2) 11 animals received DAU (3 mgykg, i.v.); (3) 5 animals received the model cardioprotective agent dexrazoxane (DEX, 60 mgykg, i.p.), 30 min prior to DAU. All substances were administered once weekly, for 10 weeks. The DAU-induced heart damage and protective action of DEX were determined and quantitated with the use of histopathology, invasive haemodynamic measurements (e.g. left ventricular pressure changes-dPydt , dPydt ), non-invasive systolic function examinations (left max min ventricular ejection fraction, PEPyLVET index) and biochemical analysis of cardiac troponin T plasma concentrations. Results: All the employed methods showed unambiguously pronounced heart impairment in the DAU group, with the development of both systolic and diastolic heart failure, as well as significant reduction of DAU-cardiotoxicity in DEX-pretreated animals. Other toxicities were acceptable. Conclusion: The presented model has been approved to be consistent and reliable and it can serve as a basis for future determinations and comparisons of chronic cardiotoxic effects of various drugs, as well as for the evaluation of potential cardioprotectants.

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. Nevertheless, in spite of vigorous research in this area, a number of questions are still unanswered and these are discussed in this review. The main problems seem to be the lack of standardisation of variety of troponin immunoassays, the assessment of suitable cutoff for drug-induced cardiotoxicity and determination of critical diagnostic window related to the optimal timing of sample collection, which may be drug-dependent.

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. Methods: Chronic anthracycline cardiotoxicity was induced in rabbits by repeated daunorubicin (DAU) administrations (3 mg kg −1 weekly for 10 weeks). Cardiomyocyte apoptosis was evaluated using TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling) assay and activities of caspases 3/7, 8, 9 and 12. Lipoperoxidation was assayed using HPLC determination of myocardial malondialdehyde and 4-hydroxynonenal immunodetection. Results: Dexrazoxane (60 mg kg −1 ) co-treatment was capable of overcoming DAU-induced mortality, left ventricular dysfunction, profound structural damage of the myocardium and release of cardiac troponin T and I to circulation. Moreover, for the first time, it has been shown that DEX affords significant and nearly complete cardioprotection against anthracycline-induced apoptosis in vivo and effectively suppresses the complex apoptotic signalling triggered by DAU. In individual animals, the severity of apoptotic parameters significantly correlated with cardiac function. However, this effective cardioprotection occurred without a significant decrease in anthracycline-induced lipoperoxidation. Conclusion: This study identifies inhibition of apoptosis as an important target for effective cardioprotection against chronic anthracycline cardiotoxicity and suggests that lipoperoxidation-independent mechanisms are involved in the cardioprotective action of DEX.

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.

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