Antitumor effect of TNP‐470, an angiogenesis inhibitor, combined with ultrasound irradiation for human uterine sarcoma xenografts evaluated using contrast color Doppler ultrasound
Antitumor effect of TNP‐470, an angiogenesis inhibitor, combined with ultrasound irradiation for human uterine sarcoma xenografts evaluated using contrast color Doppler ultrasound
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DOI：
10.1111/j.1349-7006.2007.00474.x
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发表时间：
2007-06
期刊：
影响因子：
5.7
通讯作者：
M. Emoto;K. Tachibana;H. Iwasaki;T. Kawarabayashi
中科院分区：
文献类型：
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作者：
M. Emoto;K. Tachibana;H. Iwasaki;T. Kawarabayashi
肿瘤募集的微血管内皮细胞已成为肿瘤治疗的重要靶点。本研究首先检测了血管生成抑制剂联合超声(US)照射对人肿瘤的体内抗肿瘤作用，并用微气泡超声造影剂实时彩色多普勒超声评价其血运状态。人子宫肉瘤细胞系FU-MMT-1被用于体内，因为该肿瘤是人类实体瘤中最恶性的肿瘤之一，而且它对目前使用的任何化疗药物以及放射治疗的反应都很差。在血管生成抑制剂中，TNP-470被选择用于体内研究，因为在体外的血管形成实验中，TNP-470显示出比FR118487或沙利度胺更高的抑制效果。在裸鼠皮下注射血管生成抑制剂TNP-470(30 mg/kg)后，用低强度超声(2.0W/cm2，1 MHz)照射FU-MMT-1裸鼠移植瘤，每周3次，每次4min，连续治疗8周。与非治疗组(对照组)相比，US单独治疗或TNP-470单独治疗均显示出抑制肿瘤生长的作用，并且联合治疗获得了显著增强的效果。与单独治疗和对照组相比，联合治疗显著减少了肿瘤内的血管，这一点通过彩色多普勒和免疫组织化学进行了评估。联合治疗组小鼠均未观察到副作用。这些结果表明，TNP-470对子宫肉瘤的体内抗肿瘤作用被超声辐射加速，这种联合作用可能是一种潜在的新的癌症治疗方法。(癌症科学2007；98：929-935)
Microvascular endothelial cells, which are recruited by tumors, have become an important target in cancer therapy. This study firstly examined the antitumor effect of angiogenesis inhibitor combined with ultrasound (US) irradiation for human cancer in vivo and evaluated its vascularity using color Doppler US in real time with a microbubble US contrast agent. A human uterine sarcoma cell line, FU‐MMT‐1, was used in vivo because this tumor is one of the most malignant neoplasms of the human solid tumors and it also has a poor response to any of the chemotherapeutic agents currently used, as well as to radiotherapy. In angiogenic inhibitors, TNP‐470 was selected to use in an in vivo study, because this agent showed a higher inhibitory effect in tube formation assay in vitro, than that of FR118487, or thalidomide. The FU‐MMT‐1 xenografts in nude mice were treated using US at a low‐intensity (2.0 w/cm2, 1MHZ) for 4 min three times per week each after the subcutaneous injection of TNP‐470 (30 mg/kg), an angiogenesis inhibitor, and this treatment was continued for 8 weeks. Either treatment of US alone or TNP‐470 alone showed a suppression of tumor growth, in comparison to the non‐treatment group (control), and a significantly enhanced effect was obtained using the combined treatment. A reduction in the intratumoral vascularity, which was evaluated using both color Doppler and immunohistochemistry, was significantly demonstrated using the combined treatment, in comparison to each treatment alone, and the control. No side‐effect was observed in any mice in the combined treatment group. These results suggest that the antitumor effect of TNP‐470 for uterine sarcoma was accelerated by US irradiation in vivo and this combination might be a potentially effective for new cancer therapy. (Cancer Sci 2007; 98: 929–935)