Myocardial toxicity of arsenic trioxide in a mouse model.
Myocardial toxicity of arsenic trioxide in a mouse model.
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DOI：
10.1385/ct:2:1:63
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发表时间：
2002-01-01
影响因子：
3.2
通讯作者：
Kang, Y James
中科院分区：
文献类型：
--
作者：
Li, Yan;Sun, Xiuhua;Kang, Y James
三氧化二砷治疗急性早幼粒细胞白血病(APL)疗效显著。2000年9月，TRISENOX品牌的三氧化二砷用于治疗复发和难治性急性早幼粒细胞白血病在美国获得批准。最近的一份临床报告显示，在APL患者中，治疗剂量的三氧化二砷存在严重的室性心动过速。本研究采用小鼠模型研究了三氧化二砷的心脏毒性作用。动物被注射三氧化二砷5毫克/公斤/天，连续30天，该剂量方案已被证明产生的血浆砷浓度在砷治疗的APL患者的范围内。心肌功能分析显示，砷可使心室收缩时最大室内压上升速率(Max dp/dt)显著降低，舒张末压和最低舒张压显著升高。在异丙肾上腺素的刺激下，砷处理的心脏没有表现出最大dp/dt的增加，这在生理盐水处理的对照组中被观察到是应激反应。组织病理学和超微结构检查显示，这些功能改变伴有心肌病。此外，通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记实验证实了砷对心肌细胞的凋亡作用，通过酶法检测caspase-3的激活证实了这一点。因此，我们的研究表明，三氧化二砷会引起心脏毒性，其剂量可能会产生与人类观察到的血清浓度相当的临床浓度。
Arsenic trioxide is highly effective in the treatment of acute promyelocytic leukemia (APL). In September 2000, the Trisenox brand of arsenic trioxide for the treatment of relapsed and refractory APL was approved in the United States. A recent clinical report has shown a serious ventricular tachycardia at the therapeutic doses of arsenic trioxide in APL patients. The present study was undertaken to investigate the cardiotoxic effect of arsenic trioxide using a mouse model. Animals were injected intraperitoneally with arsenic trioxide 5 mg/ kg/d for 30 d, a dose regiment that has been shown to produce plasma concentrations of arsenic within the range of those present in arsenic-treated APL patients. Analysis of myocardial function revealed that arsenic caused a significant decrease in the maximum rate of rise in intraventricular pressure during ventricular contraction (MAX dP/dt), and significant increases in the end diastolic pressure and ventricle minimum diastolic pressure. In response to B-adrenergic stimulation by isoproterenol, the arsenic-treated heart did not show increase in MAX dP/dt, which was observed as a stress response in the saline-treated controls. The functional alterations were accompanied by cardiomyopathy, as revealed by histopathological and ultrastructural examination. Furthermore, arsenic caused myocardial apoptosis, as determined by a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, which was confirmed by caspase-3 activation detected by enzymatic assay. Our study thus demonstrates that arsenic trioxide, in a dose that could produce clinically comparable serum concentrations to those observed in humans, causes cardiotoxicity.