Chlorpromazine and apigenin reduce adenovirus replication and decrease replication associated toxicity
Chlorpromazine and apigenin reduce adenovirus replication and decrease replication associated toxicity
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DOI：
10.1002/jgm.984
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发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Hemminki, Akseli
中科院分区：
文献类型：
--
作者：
Kanerva, Anna;Raki, Mari;Hemminki, Akseli
背景 腺病毒可对免疫功能低下的个体造成严重的毒性。尽管临床试验已经证实了选择性溶瘤腺病毒治疗晚期癌症的效力和安全性，但越来越有效的药物可能会导致更大的毒性，因此如果必要时能够消除复制，将是有用的。方法我们分析了氯丙嗪（一种网格蛋白依赖性内吞作用抑制剂）和芹菜素（一种细胞周期调节剂）对腺病毒复制和毒性的影响。首先，我们评估了肿瘤靶向 Rb-p16 途径选择性溶瘤腺病毒 (Ad5/3-Delta 24) 和野生型腺病毒在正常细胞、新鲜肝脏样本和卵巢癌细胞系中的体外复制。此外，我们分析了在存在和不存在这些物质的情况下腺病毒的体外细胞杀伤功效。此外，还评估了腺病毒对体内功效、复制和肝毒性的影响。结果我们证明了氯丙嗪和芹菜素在体外和体内减少了腺病毒复制和相关毒性。有效剂量完全在预测的人类安全剂量之内。 结论 氯丙嗪和芹菜素可能会减少腺病毒的复制，这可以在患者遇到复制相关副作用时提供安全转换。此外，这些物质可用于治疗免疫抑制患者的全身性腺病毒感染。版权所有 (c) 2006 John Wiley & Sons, Ltd.
Background Adenoviruses can cause severe toxicity in immunocompromised individuals. Although clinical trials have confirmed the potency and safety of selectively oncolytic adenoviruses for treatment of advanced cancers, increasingly effective agents could result in more toxicity and therefore it would be useful if replication could be abrogated if necessary.Methods We analyzed the effect of chlorpromazine, an inhibitor of clathrin-dependent endocytosis and apigenin, a cell cycle regulator, on adenovirus replication and toxicity. First, we evaluated the in vitro replication of a tumor targeted Rb-p16 pathway selective oncolytic adenovirus (Ad5/3-Delta 24) and a wild-type adenovirus in normal cells, fresh liver samples and in ovarian cancer cell lines. Further, we analyzed the in vitro cell killing efficacy of adenoviruses in the presence and absence of the substances. Moreover, the effect on in vivo efficacy, replication and liver toxicity of the adenoviruses was evaluated.Results We demonstrate in vitro and in vivo reduction of adenovirus replication and associated toxicity with chlorpromazine and apigenin. Effective doses were well within what would be predicted safe in humans.Conclusions Chlorpromazine and apigenin might reduce the replication of adenovirus, which could provide a safety switch in case replication-associated side effects are encountered in patients. In addition, these substances could be useful for the treatment of systemic adenoviral infections in immunosuppressed patients. Copyright (c) 2006 John Wiley & Sons, Ltd.