Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, 409 Tache Avenue, Winnipeg, Manitoba, Canada.
J Am Soc Echocardiogr. 2011 Jun;24(6):699-705. doi: 10.1016/j.echo.2011.01.018. Epub 2011 Feb 24.
Although the combination of doxorubicin (Dox) and trastuzumab (Trz) reduces breast cancer progression and recurrence, it is limited by significant cardiotoxic side effects. Little is known about the utility of antioxidants in the prevention of this drug-induced cardiomyopathy. The aim of the study was to determine whether the antioxidant probucol (Prob) would be useful in attenuating Dox and Trz-mediated cardiotoxicity.
A total of 114 mice were randomized to treatment with Trz, Dox, or Dox+Trz. Within each arm, mice received prophylactic treatment with placebo or Prob. Serial murine echocardiography with tissue Doppler imaging was performed daily for 10 days. At 10 days posttreatment, the hearts were removed for histopathologic and Western blot analyses.
Left ventricular cavity dimensions and systolic parameters were preserved in mice prophylactically treated with Prob after the administration of Dox+Trz. Although the combination of Dox+Trz demonstrated >80% mortality at day 5, prophylactic treatment with Prob reduced mortality to 40% at day 10. There was decreased histologic evidence of cardiac damage and reduced apoptosis due to Dox+Trz in mice pretreated with Prob.
The cardiotoxic effects of Dox+Trz are partially attenuated by the prophylactic administration of the antioxidant Prob.
多柔比星（Dox）和曲妥珠单抗（Trz）的联合应用虽然可以降低乳腺癌的进展和复发，但却受到明显的心脏毒性副作用的限制。关于抗氧化剂在预防这种药物诱导性心肌病中的作用知之甚少。本研究旨在确定抗氧化剂普罗布考（Prob）是否有助于减轻 Dox 和 Trz 介导的心脏毒性。
共 114 只小鼠随机分为 Trz、Dox 或 Dox+Trz 治疗组。在每个臂中，小鼠接受安慰剂或 Prob 的预防性治疗。连续进行 10 天的鼠超声心动图和组织多普勒成像。治疗后 10 天，取出心脏进行组织病理学和 Western blot 分析。
在接受 Dox+Trz 治疗后预防性给予 Prob 的小鼠中，左心室腔尺寸和收缩期参数得以维持。尽管 Dox+Trz 联合应用在第 5 天导致超过 80%的死亡率，但预防性给予 Prob 将第 10 天的死亡率降低至 40%。在预防性给予 Prob 的小鼠中，由于 Dox+Trz 导致的心脏损伤和细胞凋亡的组织学证据减少。
抗氧化剂 Prob 的预防性给药部分减轻了 Dox+Trz 的心脏毒性作用。
