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.

Department of Biochemical Sciences Faculty of Pharmacy in Hradec Králové Charles University Czech Republic

Department of Cardiology Royal Brompton Hospital and Faculty of Medicine National Heart and Lung Institute Imperial College London United Kingdom

Department of Histology and Embryology Faculty of Medicine in Hradec Králové Charles University Czech Republic

Department of Organic and Bioorganic Chemistry Faculty of Pharmacy in Hradec Králové Charles University Czech Republic

Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Faculty of Pharmacy in Hradec Králové Charles University Czech Republic

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Králové Charles University Czech Republic

Department of Pharmacology Faculty of Medicine in Hradec Králové Charles University Czech Republic

Department of Physiology Faculty of Medicine in Hradec Králové Charles University Czech Republic

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$a Jirkovský, Eduard $u Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., Z.P., P.K.-B., O.L.-P., M.Š.), Charles University, Czech Republic $u Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové (E.J.), Charles University, Czech Republic

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$a Clinically Translatable Prevention of Anthracycline Cardiotoxicity by Dexrazoxane Is Mediated by Topoisomerase II Beta and Not Metal Chelation / $c E. Jirkovský, A. Jirkovská, H. Bavlovič-Piskáčková, V. Skalická, Z. Pokorná, G. Karabanovich, P. Kollárová-Brázdová, J. Kubeš, O. Lenčová-Popelová, Y. Mazurová, M. Adamcová, AR. Lyon, J. Roh, T. Šimůnek, P. Štěrbová-Kovaříková, M. Štěrba

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$a 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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$a Jirkovská, Anna $u Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové (A.J., V.S., J.K., T.Š.), Charles University, Czech Republic

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$a Bavlovič-Piskáčková, Hana $u Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové (H.B.-P., P.Š.-K.), Charles University, Czech Republic

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$a Skalická, Veronika $u Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové (A.J., V.S., J.K., T.Š.), Charles University, Czech Republic

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$a Pokorná, Zuzana $u Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., Z.P., P.K.-B., O.L.-P., M.Š.), Charles University, Czech Republic

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$a Karabanovich, Galina $u Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové (G.K., J.R.), Charles University, Czech Republic

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$a Kollárová-Brázdová, Petra $u Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., Z.P., P.K.-B., O.L.-P., M.Š.), Charles University, Czech Republic

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$a Kubeš, Jan $u Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové (A.J., V.S., J.K., T.Š.), Charles University, Czech Republic

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$a Lenčová-Popelová, Olga $u Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., Z.P., P.K.-B., O.L.-P., M.Š.), Charles University, Czech Republic

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$a Mazurová, Yvona $u Department of Histology and Embryology, Faculty of Medicine in Hradec Králové (Y.M.), Charles University, Czech Republic

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$a Adamcová, Michaela $u Department of Physiology, Faculty of Medicine in Hradec Králové (M.A.), Charles University, Czech Republic

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$a Lyon, Alexander R $u Department of Cardiology, Royal Brompton Hospital and Faculty of Medicine, National Heart and Lung Institute, Imperial College London, United Kingdom (A.R.L.)

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$a Roh, Jaroslav $u Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové (G.K., J.R.), Charles University, Czech Republic

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$a Šimůnek, Tomáš $u Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové (A.J., V.S., J.K., T.Š.), Charles University, Czech Republic

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$a Štěrbová-Kovaříková, Petra $u Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové (H.B.-P., P.Š.-K.), Charles University, Czech Republic

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$a Štěrba, Martin $u Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., Z.P., P.K.-B., O.L.-P., M.Š.), Charles University, Czech Republic

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