Dexrazoxane-afforded protection against chronic anthracycline cardiotoxicity in vivo: effective rescue of cardiomyocytes from apoptotic cell death.
Dexrazoxane-afforded protection against chronic anthracycline cardiotoxicity in vivo: effective rescue of cardiomyocytes from apoptotic cell death.
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DOI：
10.1038/sj.bjc.6605192
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发表时间：
2009-09-01
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
右雷佐生（DEX，ICRF-187）是临床上唯一批准的针对蒽环类药物心脏毒性的心脏保护剂。传统上认为其水解为铁螯合剂ADR-925，并防止蒽环类药物诱导的氧化应激、进行性心肌细胞变性和随后的非程序性细胞死亡。然而，DEX保护心肌细胞免于凋亡的额外能力在临床相关的体内条件下仍然没有得到证实。通过反复给予柔红霉素（DAU）（每周3 mg/kg，持续10周）在家兔中诱导慢性蒽环类药物心脏毒性。采用TUNEL法检测心肌细胞凋亡，并检测caspase 3/7、8、9和12的活性。采用高效液相色谱法测定心肌丙二醛和4-羟基壬烯醛免疫检测法测定脂质过氧化。右雷佐生（60 mg kg−1）联合治疗能够克服DAU诱导的死亡率、左心室功能障碍、心肌严重结构损伤以及心肌肌钙蛋白T和I释放至循环。此外，第一次，已经表明DEX提供了显着的和几乎完全的心脏保护，对蒽环类药物诱导的细胞凋亡在体内，并有效地抑制复杂的细胞凋亡信号触发DAU。在个体动物中，凋亡参数的严重程度与心脏功能显著相关。然而，这种有效的心脏保护发生在没有显着减少蒽环类药物诱导的脂质过氧化。这项研究确定了细胞凋亡的抑制作为一个重要的目标，有效的心脏保护慢性蒽环类药物心脏毒性，并表明，脂质过氧化物非依赖性机制参与DEX的心脏保护作用。
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. 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. 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. 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.
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影响因子：
4.6
作者：
Arbustini, Eloisa;Brega, Agnese;Narula, Jagat
通讯作者：
Narula, Jagat
影响因子：
3.2
作者：
Hasinoff, Brian B.;Herman, Eugene H.
通讯作者：
Herman, Eugene H.
影响因子：
15.9
作者：
DOROSHOW, JH;LOCKER, GY;MYERS, CE
通讯作者：
MYERS, CE
DOI：
10.1200/jco.2007.14.9401
发表时间：
2008-08-01
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Gianni L;Herman EH;Lipshultz SE;Minotti G;Sarvazyan N;Sawyer DB
通讯作者：
Sawyer DB
影响因子：
3
作者：
Bruynzeel, Anna M. E.;Vormer-Bonne, Suzanne;van der Vijgh, Wim J. F.
通讯作者：
van der Vijgh, Wim J. F.