Long-term effects of 7-monohydroxyethylrutoside (monoHER) on DOX-induced cardiotoxicity in mice
Long-term effects of 7-monohydroxyethylrutoside (monoHER) on DOX-induced cardiotoxicity in mice
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DOI：
10.1007/s00280-006-0395-2
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发表时间：
2007-09-01
影响因子：
3
通讯作者：
van der Vijgh, Wim J. F.
中科院分区：
文献类型：
--
作者：
Bruynzeel, Anna M. E.;Vormer-Bonne, Suzanne;van der Vijgh, Wim J. F.
阿霉素 (DOX) 是一种有效的抗肿瘤药物，可治疗不同类型的癌症，但累积的、剂量相关的心脏毒性限制了其临床应用。 DOX 治疗后心功能异常的发生率似乎随着时间的推移而增加。因此，晚期心脏毒性——尤其是年轻的幸存患者——是一个主要问题。本研究的目的是在小鼠中评估半合成类黄酮 7-单羟乙基芸香苷 (monoHER) 在长期随访后是否也能预防 DOX 诱导的心脏毒性。四组每组 6 只 Balb/c 小鼠在 6 周内每周接受生理盐水、单独 DOX（4 mg/kg 静脉注射）、DOX 先用 monoHER（500 mg/kg i.p.）或 DOX 先用 monoHER 然后在 6 个月的观察期内长期每周注射 monoHER 治疗。接受 DOX 治疗的小鼠中有一半仅出现 DOX 诱导的心力衰竭，并在观察 6 个月内死亡。两只接受 monoHER 联合治疗的小鼠表现出体重减轻和呼吸短促，而一只小鼠被发现死在笼子里，体重减轻。接受 DOX 加长期重复剂量 monoHER 的组开始体重减轻。该组中六分之五的小鼠出现呼吸短促，并在研究结束前死亡，并出现 DOX 诱发的心力衰竭症状。不可能对不同实验组之间的组织学心脏损伤进行统计比较，因为动物在观察期间的不同时间点死亡，并且DOX引起的心脏毒性随着时间的推移而进展。然而，很明显，在半年的观察期内，monoHER 的初始心脏保护作用并未延长。甚至有人提出，重复剂量的 monoHER 的添加往往会加剧 DOX 引起的心脏毒性。不能排除的是，在 monoHER 不具有促氧化活性的情况下，monoHER 给药的剂量和频率对于获得最佳抗氧化活性至关重要。
Doxorubicin (DOX) is a potent antitumor agent for different types of cancer, but the cumulative, dose-related cardiotoxicity limits its clinical use. The incidence of abnormal cardiac function after treatment with DOX appears to increase with time. Therefore, late cardiotoxicity is-especially in young surviving patients-a major concern. The aim of this study was to evaluate in mice whether the semisynthetic flavonoid 7-monohydroxyethylrutoside (monoHER) also protected against DOX-induced cardiotoxicity after a long period of follow-up. Four groups of 6 Balb/c mice were treated weekly during 6 weeks with saline, DOX alone (4 mg/kg i.v.), DOX preceded by monoHER (500 mg/kg i.p.), or DOX preceded by monoHER followed by long-term weekly monoHER injections during the observation period of 6 months. Half of the mice treated with DOX only developed DOX-induced heart failure and died within 6 months of observation. Two mice co-treated with monoHER showed weight loss and shortness of breath, whereas one mouse was found dead in its cage known with weight loss. The group receiving DOX plus long-term repeated doses of monoHER started to lose weight. Five out of six mice in this group developed shortness of breath and died before the end of the study with symptoms of cardiac failure induced by DOX. Statistical comparison of the histological heart damage between the different experimental groups was not possible, because the animals died at different time-points in the observation period and DOX-induced cardiotoxicity progressed with time. Nevertheless, it was clear that the initial cardioprotective effect of monoHER was not prolonged during the half-year observation period. It was even suggested that addition of repeated doses of monoHER tended to aggravate DOX-induced cardiotoxicity. It cannot be excluded that the dose and frequency of monoHER administration is crucial in obtaining an optimal antioxidant activity without a pro-oxidant activity of monoHER.