Targeting antiangiogenesis inhibitor using antiangiogenesis molecular signals

利用抗血管生成分子信号靶向抗血管生成抑制剂

• 批准号: 15390219
• 负责人: SHICHIRI Masayoshi
• 金额: $ 9.47万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390219/
• 关键词: Antiangiogenesis signal; Endostatin; Endothelial cell migration; Endothelial cell growth; Anti-tumor effect; Endothelial apoptosis; Vascular endothelial cell; Metastasis; 血管新生; 細胞遊走; 細胞増殖

Cancer progression and metastasis depend on recruitment of new blood vessels and are characterized by oncogene-driven tumor expression of pro-angiogenic proteins. Most pro-angiogenic factors are soluble endogenous proteins and their receptors are displayed on the surface of endothelial cells. Inhibition of tumor angiogenesis suppresses experimental tumor growth, and is considered a promising new therapeutic approach to treat human cancer. However, clinical application of anti-angiogenesis therapy for suppression of tumor progression would theoretically require long-term administration of angiogenesis inhibitors, but most of them entering clinical trials are rather large molecular weight protein and/or require intravenous administration. We have previously demonstrated that an anti-angiogenesis inhibitor, endostatin, markedly down regulates a variety of growth-, migration-, and angiogenesis-associated genes in exponentially growing human and rat microvascular endothelial cells. In the present study, we searched for compounds and peptides eliciting such anti-angiogenesis molecular signals in endothelial cells in an attempt to identify new therapeutic agents for human tumors. The results demonstrate that three ansamycin antibiotics and a fragment of vasoactive peptide induced antiangiogenesis signals similar to endostatin and that the former suppressed progression of human cancer xenografts as well.

癌症进展和转移取决于新血管的募集，其特征是癌基因驱动的促血管生成蛋白的肿瘤表达。大多数促血管生成因子是可溶性内源性蛋白质，其受体展示在内皮细胞的表面。抑制肿瘤血管生成可抑制实验性肿瘤生长，被认为是治疗人类癌症的一种有前途的新治疗方法。然而，临床应用抗血管生成疗法抑制肿瘤进展，理论上需要长期施用血管生成抑制剂，但进入临床试验的大多是分子量较大的蛋白质和/或需要静脉注射。我们之前已经证明，抗血管生成抑制剂内皮抑素显着下调指数生长的人和大鼠微血管内皮细胞中的多种生长、迁移和血管生成相关基因。在本研究中，我们寻找在内皮细胞中引发此类抗血管生成分子信号的化合物和肽，试图识别人类肿瘤的新治疗剂。结果表明，三种安莎霉素抗生素和血管活性肽片段诱导了与内皮抑素类似的抗血管生成信号，并且前者也抑制了人类癌症异种移植物的进展。

项目成果

Shichiri M: "Salusins ; newly identified bioactive peptides with hemodynamic and mitogenic activities"Nature Medicine. 9. 1166-1172 (2003)

Shichiri M：“Salusins；新鉴定的具有血流动力学和促有丝分裂活性的生物活性肽”《自然医学》。

Fukai N: "Coexpresssion of calcitonin receptor-like receptor and receptor activity-modifying protein 2 or 3 mediates the antimigratory effect of adrenomedullin"Endocrinology. 144. 447-453 (2003)

Fukai N：“降钙素受体样受体和受体活性修饰蛋白 2 或 3 的共表达介导肾上腺髓质素的抗迁移作用”内分泌学。

Matsushita M: "Urotensin II is an autocrine/paracrine growth factor for porcine renal epithelial cell line LLCPK1"Endocrinology. 144. 1825-1831 (2003)

Matsushita M：“尾加压素 II 是猪肾上皮细胞系 LLCPK1 的自分泌/旁分泌生长因子”内分泌学。

Shichiri M: "Adrenomedullin is an autocrine/paracrine growth factor for rat vascular smooth muscle cells"Regulatory Peptides. 112. 167-173 (2003)

Shichiri M：“肾上腺髓质素是大鼠血管平滑肌细胞的自分泌/旁分泌生长因子”调节肽。

Laminar shear stress upregulates inducible nitric oxide synthase in the endothelium.

层流剪切应力上调内皮细胞中的诱导型一氧化氮合酶。

• 发表时间: 2004
• 期刊: Hypertens Res-Clinical & Experimental. 27
• 作者: Ozawa N;Shichiri M;Iwashina M;Fukai N;Yoshimoto T;Hirata Y
• 通讯作者: Hirata Y