Novel adjuvant therapy for malignant primary bone tumor using combination of anti-angiogenic reagent and bisphosphonate

抗血管生成剂与双膦酸盐联合治疗恶性原发性骨肿瘤的新型辅助治疗

• 批准号: 17591596
• 负责人: MORII Takeshi
• 金额: $ 2.24万
• 依托单位: Kyorin University (2006)Keio University (2005)
• 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-17591596/
• 关键词: Osteosarcoma; Chondrosarcoma; Angiogenesis; Bisphosphonate; 原発性悪性骨腫瘍

In vitro direct inhibition effect of alendronate on chondrosarcoma and osteosarcoma growth was confirmed. This effect was through the inhibition of ras-mevalonate pathway. By using proteome analysis with confirmation by Western blot, intracellular mechanism of this phenomenon was by apoptosis induction, cell cycle arrest and inhibition of phosphorylation on cytoskeleton proteins. Inhibition of migration of tumor cells was induced by bisphosphonate. Direct inhibition effect of endothelial cell growth in vitro was shown, also through the mevalonate pathway. Co-culture system of endothelial cells and fibroblast was established. Inhibition effect by alendronate on endothelial growth, migration, tube formation and branching was confirmed in this system without harming normal fibroblasts, suggesting the safety application of this reagent on human. Novel antiangiogenic protein, plasminogen related protein B was generated by cloning plasminogen related gene B and confirmed its antiangiogenic effect in vitro and in vivo. This effect was through the inhibition of phosphorylation of MAPK. Possible receptor of this protein was shown to be alpha VbetaII integrin on the cell surface.

体外证实了阿仑膦酸钠对软骨肉瘤和骨肉瘤生长的直接抑制作用。这种作用是通过抑制 ras-甲羟戊酸途径实现的。通过蛋白质组分析和蛋白质印迹证实，这种现象的细胞内机制是通过诱导细胞凋亡、细胞周期停滞和抑制细胞骨架蛋白的磷酸化。双膦酸盐诱导肿瘤细胞迁移的抑制。体外显示了对内皮细胞生长的直接抑制作用，也是通过甲羟戊酸途径。建立了内皮细胞与成纤维细胞共培养体系。在此系统中证实了阿仑膦酸钠对内皮生长、迁移、管形成和分支的抑制作用，且不伤害正常成纤维细胞，表明该试剂在人体上的安全应用。通过克隆纤溶酶原相关基因B产生新型抗血管生成蛋白纤溶酶原相关蛋白B，并在体外和体内证实了其抗血管生成作用。这种作用是通过抑制 MAPK 的磷酸化实现的。该蛋白质的可能受体是细胞表面的 α VbetaII 整合素。

项目成果

Autograft of pasturalized bone for the reconstruction of bone and soft tissue sarcoma resection(in Japanese)

自体巴氏骨移植用于骨重建和软组织肉瘤切除（日语）

• 发表时间: 2005
• 期刊: Bessatu seikeigeka 47
• 作者: U.Anazawa;T Morii et al.
• 通讯作者: T Morii et al.

Surgery for metastatic bone tumor (in Japanese)

转移性骨肿瘤的手术（日语）

• 发表时间: 2007
• 期刊: Jap J Orthop Assoc 81
• 作者: Y.Suzuki;T Morii et al.
• 通讯作者: T Morii et al.

Reconstruction of the extensor mechanism following malignant bone tumor resection(in Japanese)

恶性骨肿瘤切除后伸肌机构的重建（日文）

• 发表时间: 2006
• 期刊: Kotukansetujintai 19
• 作者: K. Adachi;T. Tsururnoto;et. al.;Morii T et al.
• 通讯作者: Morii T et al.

Chondromyxoid fibroma of the sternum.

胸骨软骨粘液样纤维瘤。

• 发表时间: 2006
• 期刊: J Thorac Cardiovasc Surg. 132
• 作者: Takao E;Morii T et al.
• 通讯作者: Morii T et al.

血管新生阻害薬を用いた関節炎治療

使用血管生成抑制剂治疗关节炎

• 发表时间: 2005
• 期刊: 整形外科 56
• 作者: 田中公一朗;森岡秀夫 他
• 通讯作者: 森岡秀夫 他