Dexrazoxane is clinically used to reduce doxorubicin cardiotoxicity and anthracycline-induced extravasation injury. Dexrazoxane is a strong catalytic inhibitor of topoisomerase II. It can also undergo metabolism to form an iron-binding analog of EDTA. Dexrazoxane was originally thought to act by reducing iron-dependent doxorubicin-based oxidative stress. However, a competing hypothesis posits that dexrazoxane may be protective through its ability to inhibit and reduce topoisomerase IIβ protein levels in the heart. A primary neonatal rat myocyte model was used to study the mechanism by which dexrazoxane protects against doxorubicin-induced myocyte damage. This study characterized the kinetics of the rapid and nearly complete dexrazoxane-induced loss of topoisomerase IIβ protein from neonatal rat cardiac myocytes. Immunofluorescent staining of attached myocytes for topoisomerase IIβ revealed that most of the topoisomerase IIβ was localized to the nucleus, although it was also present in the cytoplasm. Dexrazoxane treatment resulted in an almost complete reduction of topoisomerase IIβ in the nucleus and a lesser reduction in the cytoplasm. The recovery of topoisomerase IIβ levels after a pulse topoisomerase IIβ inhibitory concentration of dexrazoxane occurred slowly, with partial recovery only occurring after 24 h. The ability of dexrazoxane to reduce doxorubicin-induced damage to myocytes was greatest when topoisomerase IIβ levels were at their lowest.

中文翻译：

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拓扑异构酶IIβ在阿霉素心脏保护剂Dexrazoxane的作用机制中的作用。

右雷佐生在临床上用于减少阿霉素的心脏毒性和蒽环类药物引起的外渗损伤。右雷佐生是拓扑异构酶II的强催化抑制剂。它还可以进行新陈代谢以形成EDTA的铁结合类似物。最初认为Dexrazoxane可通过减少铁依赖性的基于阿霉素的氧化应激来发挥作用。然而，一个相互竞争的假设认为，右雷佐生可能通过抑制和降低心脏中拓扑异构酶IIβ蛋白的水平而具有保护作用。使用主要的新生大鼠心肌细胞模型来研究右雷佐生预防阿霉素诱导的心肌细胞损伤的机制。这项研究的特点是快速和几乎完全由右雷佐生引起的新生大鼠心脏心肌细胞拓扑异构酶IIβ蛋白丢失的动力学。附着的心肌细胞对拓扑异构酶IIβ的免疫荧光染色显示，尽管拓扑异构酶IIβ也存在于细胞质中，但大多数拓扑异构酶IIβ都位于细胞核内。右雷佐生处理导致细胞核中拓扑异构酶IIβ几乎完全减少，而细胞质减少较少。右雷佐生的脉冲拓扑异构酶IIβ抑制浓度后，拓扑异构酶IIβ水平的恢复缓慢发生，仅在24小时后才发生部分恢复。当拓扑异构酶IIβ水平最低时，右雷佐生减少阿霉素诱导的对心肌细胞的损害的能力最大。右雷佐生处理导致细胞核中拓扑异构酶IIβ几乎完全减少，而细胞质减少较少。右雷佐生的脉冲拓扑异构酶IIβ抑制浓度后，拓扑异构酶IIβ水平的恢复缓慢发生，仅在24小时后才发生部分恢复。当拓扑异构酶IIβ水平最低时，右雷佐生减少阿霉素诱导的对心肌细胞的损害的能力最大。右雷佐生处理导致细胞核中拓扑异构酶IIβ几乎完全减少，而细胞质减少较少。右雷佐生的脉冲拓扑异构酶IIβ抑制浓度后，拓扑异构酶IIβ水平的恢复缓慢发生，仅在24小时后才发生部分恢复。当拓扑异构酶IIβ水平最低时，右雷佐生减少阿霉素诱导的对心肌细胞的损害的能力最大。