Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer.
Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer.
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TNP-470 在甲状腺未分化癌中诱导的肿瘤细胞毒性和内皮 Rac 抑制。
DOI：
10.1158/1535-7163.mct-06-0554
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发表时间：
2007
影响因子：
5.7
通讯作者：
Nwariaku,FiemuE
中科院分区：
文献类型：
--
作者：
Nahari,Dorit;Satchi-Fainaro,Ronit;Chen,Ming;Mitchell,Ian;Task,LaurieB;Liu,Zijuan;Kihneman,Jason;Carroll,AllisonB;Terada,LanceS;Nwariaku,FiemuE
甲状腺未分化癌是一种侵袭性癌症，无法治疗。血管生成抑制剂，如烟曲霉素的合成衍生物TNP-470，已显示在甲状腺癌的异位动物模型中减小肿瘤大小并增加存活率。我们的目标是使用原位小鼠模型确定TNP-470对间变性甲状腺癌的作用，以鉴定TNP-470对内皮细胞作用的分子途径，并确定TNP-470的非内皮肿瘤作用。将人甲状腺未分化癌细胞（DRO′90）接种于裸鼠甲状腺内。小鼠接受TNP-470（30 mg/kg）s.c. 6周。TNP-470延长生存期并减少肝转移。TNP-470对甲状腺未分化癌细胞有直接的细胞毒作用。特别是，TNP-470在体外和体内均能增加肿瘤细胞血管内皮生长因子的分泌，但肿瘤微血管密度无相关增加。在内皮细胞中，TNP-470通过阻止Rac 1激活来阻止血管内皮生长因子诱导的内皮通透性、细胞间间隙形成和皱褶形成。[Mol癌症治疗2007;6（4）：1329-37]
Anaplastic thyroid carcinoma is an aggressive form of cancer with no treatment. Angiogenesis inhibitors, such as TNP-470, a synthetic derivative of fumagillin, have been shown to reduce tumor size and increase survival in heterotopic animal models of thyroid cancer. Our goals were to determine the effect of TNP-470 on anaplastic thyroid cancer using an orthotopic murine model, to identify the molecular pathways of TNP-470 actions on endothelial cells, and to determine the non-endothelial tumor effects of TNP-470. We injected human anaplastic thyroid carcinoma cells (DRO′90) into the thyroid glands of nude mice. Mice received TNP-470 (30 mg/kg) s.c. for 6 weeks. TNP-470 prolonged survival and reduced liver metastases. TNP-470 had direct cytotoxic effects on anaplastic thyroid carcinoma cellsin vitroandin vivo. Paradoxically, TNP-470 increased vascular endothelial growth factor secretion from tumor cellsin vitroandin vivo.However, there was no associated increase in tumor microvessel density. In endothelial cells, TNP-470 prevented vascular endothelial growth factor–induced endothelial permeability, intercellular gap formation, and ruffle formation by preventing Rac1 activation. [Mol Cancer Ther 2007;6(4):1329–37]