부산대학교 도서관

Anthracycline cardiotoxicity has traditionally been attributed to iron-catalysed direct oxidative injury. Dexrazoxane, the only cardio protectant approved for this indication, was thought to prevent cardiotoxicity via its metal-chelating metabolite ADR-925. However, this hypothesis lacks direct supporting evidence and was recently challenged by the topoisomerase IIß (TOP2B) hypothesis. This study thoroughly examined the putative role of iron-chelating metabolites in dexrazoxane cardio protection and investigated alternative TOP2B-related mechanisms. We performed a pharmacokinetically guided study on the protective effects of dexrazoxane and exogenously administered ADR-925 against daunorubicin-induced cardiotoxicity in vitro in neonatal ventricular cardiomyocytes (NVCM) and in vivo in a chronic rabbit model. Next, we compared the effects of dexrazoxane and ADR-925 on TOP2B and assessed daunorubicin-induced DNA damage. The intracellular concentrations of ADR-925 in NVCMs and rabbit hearts after treatment with exogenous ADR-925 were similar to or greater than those observed after treatment with the parent compound dexrazoxane. However, treatment with ADR-925 and intermediate metabolites of DEX provided no significant cardio protection against anthracycline cardiotoxicity, whereas dexrazoxane exhibited high cardioprotective efficiency. Unlike dexrazoxane, ADR-925 did not prevent daunorubicin-induced mortality, heart failure, an increase in cardiac troponin T levels in plasma, or myocardial histopathology. Dexrazoxane, but not ADR-925, inhibited and depleted TOP2B and prevented daunorubicin-induced genotoxic damage. TOP2B dependency of the cardioprotective effects was probed and further supported with diastereomers of a close DEX derivative. This study strongly supports a new mechanistic paradigm that attributes clinically relevant cardio protection against anthracycline cardiotoxicity to interactions with TOP2B, but not metal chelation and protection against direct oxidative damage. [ABSTRACT FROM AUTHOR]