Cusack B J, Gambliel H, Musser B, Hadjokas N, Shadle S E, Charlier H, Olson R D
Research Service, VA Medical Center (111), 500 W Fort St, Boise, ID, 83702, USA.
Cancer Chemother Pharmacol. 2006 Oct;58(4):517-26. doi: 10.1007/s00280-006-0199-4. Epub 2006 Mar 23.
Anthracyclines, such as doxorubicin and daunorubicin, continue to be widely used in the treatment of cancer, although they share the adverse effect of chronic, cumulative dose-related cardiotoxicity. The only approved treatment in prevention of anthracycline cardiotoxicity is dexrazoxane, a putative iron chelator. Previous in vitro studies have shown that disorders of iron metabolism, including altered IRP1-IRE binding, may be an important mechanism of anthracycline cardiotoxicity.
This study examined the role of IRP1-IRE binding ex vivo in a chronic model of daunorubicin cardiotoxicity in the Fischer 344 rat and whether dexrazoxane could prevent any daunorubicin-induced changes in IRP1 binding. Young adult (5-6 months) Fischer 344 rats received daunorubicin (2.5 mg/kg iv once per week for 6 weeks) with and without pretreatment with dexrazoxane (50 mg/kg ip). Other groups received saline (controls) or dexrazoxane alone. Rats were killed either 4 h or 2 weeks after the last dose of daunorubicin to assess IRP1-IRE binding.
Contractility (dF/dt) of atrial tissue, obtained from rats 2 weeks after the last dose of daunorubicin, was significantly reduced in daunorubicin-treated compared to control rats. Dexrazoxane pretreatment protected against the daunorubicin-induced decrease in atrial dF/dt. However, left ventricular IRP1/IRE binding was not affected by daunorubicin treatment either 4 h or 2 weeks after the last dose of daunorubicin.
IRP1 binding may not be altered in the rat model of chronic anthracycline cardiotoxicity.
蒽环类药物，如多柔比星和柔红霉素，尽管具有慢性、累积剂量相关的心脏毒性这一不良反应，但仍被广泛用于癌症治疗。预防蒽环类药物心脏毒性的唯一获批治疗方法是右丙亚胺，一种假定的铁螯合剂。先前的体外研究表明，铁代谢紊乱，包括IRP1-IRE结合改变，可能是蒽环类药物心脏毒性的重要机制。
本研究在Fischer 344大鼠柔红霉素心脏毒性慢性模型中，研究了IRP1-IRE结合在体外的作用，以及右丙亚胺是否能预防柔红霉素诱导的IRP1结合变化。年轻成年（5-6个月）Fischer 344大鼠接受柔红霉素（2.5 mg/kg静脉注射，每周一次，共6周），部分大鼠在注射柔红霉素前接受右丙亚胺预处理（50 mg/kg腹腔注射）。其他组接受生理盐水（对照组）或单独的右丙亚胺。在最后一剂柔红霉素给药后4小时或2周处死大鼠，以评估IRP1-IRE结合情况。
与对照大鼠相比，在最后一剂柔红霉素给药2周后，从大鼠获取的心房组织收缩性（dF/dt）在柔红霉素治疗组显著降低。右丙亚胺预处理可防止柔红霉素诱导的心房dF/dt降低。然而，在最后一剂柔红霉素给药后4小时或2周，左心室IRP1/IRE结合不受柔红霉素治疗影响。
在慢性蒽环类药物心脏毒性大鼠模型中，IRP1结合可能未发生改变。
