Metronomic scheduling of a cyclic hexapeptide Ra-VII for anti-angiogenesis, tumor vessel maturation and anti-tumor activity
Metronomic scheduling of a cyclic hexapeptide Ra-VII for anti-angiogenesis, tumor vessel maturation and anti-tumor activity
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DOI：
10.1111/j.1349-7006.2006.00229.x
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发表时间：
2006-07-01
期刊：
影响因子：
5.7
通讯作者：
Sato, Yasufumi
中科院分区：
文献类型：
--
作者：
Koizumi, Takayuki;Abe, Mayumi;Sato, Yasufumi
RA-VII是从芸香中分离的环状六肽，与肌动蛋白结合，引起肌动蛋白分子的构象变化，并通过抑制胞质分裂诱导G（2）阻滞。在这里，我们研究了RA-VII，其水溶性衍生物，以及相关的RA-III和RA-V对内皮细胞的影响。在测试的四种化合物中，RA-VII在体外最有效地抑制内皮细胞的血管生成相关性质（即迁移和增殖）。我们通过使用小鼠角膜模型证实了RA-VII在体内的抗血管生成活性。然后，我们应用RA-VII治疗小鼠肿瘤。每天腹腔注射RA-VII（1.5或3 mg/kg/天）对动物无毒性作用，但显著且剂量依赖性地抑制预先接种到小鼠中的刘易斯肺癌细胞的生长。有趣的是，尽管两个剂量的RA-VII将肿瘤血管面积降低到相似的程度，但较高剂量的RA-VII导致肿瘤血管成熟以及肿瘤细胞凋亡的显著增加。此外，RA-VII显示出对刘易斯肺癌细胞的细胞毒性作用。这些结果表明RA-VII的节拍调度对于癌症治疗是有效的。RA-VII的仔细剂量设定对于获得治疗优势是至关重要的，可能通过肿瘤血管成熟和化合物在肿瘤组织中的更好分布。
RA-VII, a cyclic hexapeptide isolated from Rubiae radix, binds to actin, causing a conformational change in the actin molecule and inducing G(2) arrest by inhibiting cytokinesis. Here we examined the effect of RA-VII, its water-soluble derivative, and related RA-III and RA-V on endothelial cells. Among the four compounds tested, RA-VII most potently inhibited angiogenesis-related properties of endothelial cells (i.e. migration and proliferation) in vitro. We confirmed the anti-angiogenic activity of RA-VII in vivo by using a mouse corneal model. We then applied RA-VII for the treatment of tumors in mice. Daily intraperitoneal injection of RA-VII (1.5 or 3 mg/kg/day) exhibited no toxic effect on the animals, but significantly and dose dependently inhibited the growth of Lewis lung carcinoma cells previously inoculated into the mice. Interestingly, although two doses of RA-VII decreased the tumor vascular area to a similar extent, a higher dose of RA-VII led to tumor vessel maturation together with a significant increase in tumor cell apoptosis. Also, RA-VII showed a cytotoxic effect on Lewis lung carcinoma cells. These results indicate that metronomic scheduling of RA-VII is efficient for cancer treatment. A careful dose setting of RA-VII is crucial to obtain therapeutic superiority, possibly through tumor vessel maturation and a better distribution of the compound in the tumor tissue.