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Development of molecular targeted therapy for malignant pleural mesothelioma

恶性胸膜间皮瘤分子靶向治疗的进展

基本信息

批准号：
17590792
负责人：
YANO Seiji
金额：
$ 2.24万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590792/
关键词：
malignant pleural mesothelioma orthotopic implantation model pleural effusion VEGF resistance to anticancer drugs EGF receptor MYO18B

项目摘要

Malignant pleural mesothelioma (MPM) grows aggressively with dissemination in the thoracic cavity and frequently produces malignant pleural effusion. MPM causes respiratory symptoms, including dyspnea, shortness of breath and chest pain, which thus severely limits the quality of life in patients with this disease. Since MPM is refractory to conventional chemotherapy and radiotherapy, the prognosis of MPM patients is extremely poor. To develop a novel therapeutic approach, the cellular and molecular pathogenesis of MPM should be clarified. For such purposes, we established a suitable animal model of MPM that shows patient-like tumor progression. A human MPM cell line (EHMES-10) inoculated orthotopically (thoracic cavity) into SCID mice produced highly vascularized thoracic tumors with pleural dissemination and bloody pleural effusions by 5 weeks.MYO18B, a novel member of the myosin family, is a tumor suppressor gene isolated from a homozygously deleted region at 22q12.1 in a lung cancer … More cell line. The inactivation of the MYO18B gene plays an important role in several malignant diseases. However, the role of MYO18B in the progression of MPM is still unknown. Six different human MPM cell lines were used in this study. Western blot revealed that none of the cell lines expressed a detectable level of MYO18B protein. One of the MPM cell lines, EHMES-10, was transfected with the MYO18B gene. We found that a restored expression of the MYO18B protein in EHMES-10 cells resulted in the inhibition of their anchorage-independent growth and motility in vitro. In addition, it also inhibited their ectopic (subcutaneous space) and orthotopic (thoracic cavity) growth in SCID mice, in association with an increased degree of cell-apoptosis. Furthermore, it also suppressed the production of bloody pleural effusion after orthotopic injection. These findings suggest that the restored expression of MYO18B may be a useful therapeutic strategy for the treatment of locally advanced MPM in humans. Less

恶性胸膜间皮瘤（MPM）在胸腔内侵袭性生长并扩散，经常引起恶性胸腔积液。MPM引起呼吸道症状，包括呼吸困难、呼吸短促和胸痛，因此严重限制了患有这种疾病的患者的生活质量。由于MPM是难治性的常规化疗和放疗，MPM患者的预后极差。为了开发一种新的治疗方法，MPM的细胞和分子发病机制应该澄清。为此，我们建立了一个合适的动物模型MPM，显示病人样肿瘤进展。将人MPM细胞系（EHMES-10）原位（胸腔）接种到SCID小鼠体内，5周后产生高度血管化的胸腔肿瘤，伴胸膜播散和血性胸腔积液。MYO 18 B是肌球蛋白家族的一个新成员，是从肺癌22q12.1同源缺失区分离的抑癌基因 ...更多信息细胞系MYO 18 B基因的失活在几种恶性疾病中起重要作用。然而，MYO 18 B在MPM进展中的作用仍然未知。本研究中使用了六种不同的人MPM细胞系。Western blot结果显示，所有细胞系均未表达可检测水平的MYO 18 B蛋白。用MYO 18 B基因转染MPM细胞系之一EHMES-10。我们发现，MYO 18 B蛋白在EHMES-10细胞中的恢复表达导致其在体外的锚定非依赖性生长和运动的抑制。此外，它还抑制其异位（皮下空间）和原位（胸腔）生长在SCID小鼠，与细胞凋亡程度增加。此外，它还抑制原位注射后血性胸腔积液的产生。这些发现表明MYO 18 B的恢复表达可能是治疗人类局部晚期MPM的有用治疗策略。少