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Development of inhibitors for a angiogenesis factor CTGF and its application for angiogenetic diseases

血管生成因子CTGF抑制剂的研制及其在血管生成疾病中的应用

基本信息

批准号：
10557165
负责人：
TAKIGAWA Masaharu
金额：
$ 8.77万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

1) As inhibitors for connective tissue growth factor (CTGF), a polyclonal antibody was raised by immunizing a synthesis CTGF fragment into rabbit. In addition, monoclonal anti-CTGF antibodies were also prepared.2) Recombinant CTGF (rCTGF) promoted the adhesion, proliferation and migration of the vascular endothelial cells and these effects were inhibited by anti-CTGF antibody.3) rCTGF markedly induced the tube formation of vascular endothelial cells, and this effect was stronger than that of basic fibroblast growth of vascular endothelial growth factor.4) Application of rCTGF to the chicken chrioallantoic membrane (CAM) resulted in gross angiogenic response and the effect was inhibited by anti-CTGF antibody. rCTGF injected with collagen gels into the back of mice induced strong angiogenesis in vivo.5) Among three cell lines (breast cancer cell line MDA231, fibrosarcoma cell line HT1080 and squamous carcinoma cell line A431), the ability to produce CTGF was highest in MDA231 and lowest in A431 and was parallel to their ability to form angiogenic tumors in nude mice. Anti-CTGF antibody inhibited tumor-induced angiogenesis in CAM.6) CTGF was present in synovial fluid in patients with rheumatoid arthritis which is an angiogenic decease.7) CTGF was expressed in the infarct zone of experimentally induced myocardial infarction in rats.8) Human anti-CTGF antibodies were raised in transgenic mice producing human type antibody. One of them inhibited bone metastasis of MDA231 tumors which produce much CTGF.These findings indicate that CTGF is a novel, potent angiogenesis factor which functions in multi-stages in physiological and pathological angiogenesis and suggest that anti-CTGF antibody can be used as an inhibitor for angiogenesis.

1)作为结缔组织生长因子（CTGF）的抑制剂，将合成的CTGF片段免疫兔，制备了多克隆抗体。2）重组CTGF（rCTGF）能促进血管内皮细胞的粘附、增殖和迁移，抗CTGF抗体可抑制rCTGF的这种作用; 3）rCTGF能显著诱导血管内皮细胞的管腔形成，并且这种作用强于碱性成纤维细胞生长的血管内皮生长因子。4）rCTGF在鸡胚尿囊膜（CAM）上的应用结果显示，该作用可被抗CTGF抗体所抑制。5）乳腺癌细胞系MDA 231、纤维肉瘤细胞系HT 1080和鳞癌细胞系A431中，MDA 231产生CTGF的能力最强，A431最低，且与裸鼠体内形成血管生成肿瘤的能力相平行。抗CTGF抗体可抑制CAM中肿瘤诱导的血管生成。6）CTGF存在于类风湿性关节炎患者的滑液中，类风湿性关节炎是一种血管生成性疾病。7）CTGF在实验诱导的大鼠心肌梗死的梗死区中表达。8）人抗CTGF抗体在产生人型抗体的转基因小鼠中产生。这些结果表明，CTGF是一种新的、强有力的血管生成因子，在生理和病理血管生成的多个阶段发挥作用，提示抗CTGF抗体可作为血管生成的抑制剂。