Approved oncology drugs lack in vivo activity against Trichuris muris despite in vitro activity
Approved oncology drugs lack in vivo activity against Trichuris muris despite in vitro activity
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DOI：
10.1007/s00436-016-5225-9
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发表时间：
2016-11-01
影响因子：
2
通讯作者：
Keiser, Jennifer
中科院分区：
文献类型：
--
作者：
Cowan, Noemi;Raimondo, Alessia;Keiser, Jennifer
土源性蠕虫（STH）感染被认为是最持久的全球健康问题之一。少数可用药物具有局限性，包括对鞭毛虫感染的功效较低。作为药物重新定位的起点，我们研究了一系列 FDA 批准的针对鼠鞭虫活性的肿瘤药物，因为与癌症治疗相关的靶标可能在蠕虫生物学中具有功能。对鼠毛虫幼虫和成虫阶段的药物进行了体外测试。在 T. muris 小鼠模型中以 200-400 mg/kg 的单次口服剂量测试了具有体外活性的化合物。在体外测试的 114 种药物中，有 12 种显示出针对鼠毛虫幼虫的活性（50 μM 时药效> 80%）。其中10种药物在成虫阶段也有活性（50μM时药效>80%），其中6种的IC50值在1.8至5.0μM之间。除枸橼酸他莫昔芬外，所有体外活性药物均为蛋白激酶抑制剂。体内测试的药物均未显示出功效，显示蠕虫负荷减少了 0-24%，蠕虫排出率为 0-7.9%。蛋白激酶的有前途的体外活性无法在体内得到证实。应加强针对 STH 的药物发现，包括化合物进展标准的定义。可以考虑对修饰化合物进行后续结构-活性关系研究。
Infections with soil-transmitted helminths (STHs) are considered among the most persistent global health problems. The few available drugs have limitations including low efficacy against Trichuris trichiura infections. As a starting point toward drug repositioning, we studied a set of FDA-approved oncology drugs for activity against Trichuris muris since targets relevant to cancer therapy might have a function in helminth biology. Drugs were tested in vitro on the larval and adult stage of T. muris. Compounds active in vitro were tested in the T. muris mouse model at single oral dosages of 200-400 mg/kg. Of the 114 drugs tested in vitro, 12 showed activity against T. muris larvae (> 80 % drug effect at 50 mu M). Ten of these drugs were also active on the adult worm stage (> 80 % drug effect at 50 mu M), of which six revealed IC50 values between 1.8 and 5.0 mu M. Except for tamoxifen citrate, all in vitro active drugs were protein kinase inhibitors. None of the drugs tested in vivo showed efficacy, revealing worm burden reductions of 0-24 % and worm expulsion rates of 0-7.9 %. The promising in vitro activities of protein kinases could not be confirmed in vivo. Drug discovery against STH should be strengthened including the definition of compound progression criteria. Follow-up structure-activity relationship studies with modified compounds might be considered.