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.

中文翻译：

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右雷佐生对蒽环类药物心脏毒性的临床可转化预防是由拓扑异构酶 II Beta 介导的，而不是金属螯合

背景：蒽环类药物引起的心力衰竭传统上归因于直接铁催化的氧化损伤。Dexrazoxane (DEX)——唯一被批准用于预防的药物——被认为通过其铁螯合代谢物 ADR-925 保护心脏。然而，缺乏直接证据，最近提出的TOP2B（拓扑异构酶IIβ）假说挑战了最初的概念。机械实验。柔红霉素对体外新生心室心肌细胞和体内慢性兔模型（n = 50）诱导心脏毒性。 结果：外源性 ADR-925 治疗后新生儿心室心肌细胞和兔心脏中 ADR-925 的细胞内浓度与亲本 DEX 治疗后观察到的相似或超过。然而，ADR-925 不能保护新生儿心室心肌细胞免受蒽环类药物的毒性，而 DEX 表现出显着的保护作用（10-100 µmol/L；P <0.001）。与 DEX 不同，ADR-925 对柔红霉素诱导的死亡率、血液充血以及体内心功能不全的生化和功能标志物也没有显着影响（例如，终点左心室缩短分数为 32.3±14.7%、33.5±4.8%、柔红霉素、ADR-925 [120 mg/kg]+柔红霉素、DEX [60 mg/kg]+柔红霉素和对照组分别为 42.7±1.0% 和 41.5±1.1%；P<0.05）。DEX，但不是 ADR-925，抑制和消耗 TOP2B 并防止柔红霉素诱导的基因毒性损伤。心脏保护作用的 TOP2B 依赖性得到了新 DEX 衍生物非对映异构体实验的探索和支持。氧化损伤。