A Study of an anti-angiogenic thcropy targetting integrins expressed on angiogenesis endotherial cells

靶向血管生成内皮细胞表达的整合素的抗血管生成细胞的研究

• 批准号: 09671278
• 负责人: SUNAMURA Makoto
• 金额: $ 1.86万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671278/
• 关键词: angiogenesis; microenvironment; matrix metalloproteinase; IL-12; E-selectin; VEGF; Eセレクテン; αvβ3; TNP-470; 腫瘍

Interleukin 12(IL-12) was proved to induce a potent antitumor and antimetastasis immune response in different models. It had also been reported that IL-12 possess anti-angiogenesis effect. The aim of this study is to clarify the anti-angiogenesis effect of IL-12 on human pancreatic carcinoma using a vital microscope system. We used severe combined immune-deficient mice (SCID). Skinfold chamber models was used to evaluate tumor growth and angiogenesis after implantation of PK-1 (pancreatic carinoma cells) or IL-12 genetically engineered PK-1 (IL-12/PK-1). Images of neovascularization were recorded though intravital microscopy and analyzed off-line. The effects of anti-IFNy and anti-IL-12 antibodies were investigated. Anti-asialo GM1 antibodi was injected to block the natural immunity. Although there was no asialo GMI antibody was injected to block the natural immunity differences in growth curve in vitro between PK-1 and IL-12/PK-.1, the growth of IL-12/PK-1 was inhibited significantly … More as compared with PK-1 in vivo. Skinfold chamber studies showed a strong inhibition on tumor an giogenesis of IL-12/PL-1. IL-12 antibodies administration allowed tumor development after IL-12/PK-1 implantation. It is demonstrated that anti-angiogenesis effect of IL-12 prevented the growth of panaoreatic cancer. Local delivery system of IL-12 is expected to a new strategy for pancreatic cancer.CD62E (B-selectin, SLAM,1) expressed on endothelial cells can bind to its ligands sLeas and sLex on the surface of tumor cells. The soluble form of E-selectin was also found to promote inflammation and tumor angiogenesis. In order to study the role of CD62E in tumor microenviroment. we isolated CD62B cDNA from murine C-26 colon adcnocardnoma cell line which we found to express CD62B by FACScan. CD62E cDNA was transfected into mudne B16 melanoma cell line (B 16/B) which does not express CD62B.There was no difference between the in vibo growth of B16/E and B16 lines. The B16/E tumors grew faster than B16 tumors paralleled by rapid neovascularization when tumors were grown within the transparent chambers in SCID mice. When a new synthetic antagonist of selections, KB-R9188 was administered i-p-daily (10 mg/kg) for 20 days to SCID mico, the growth of B16/B tumores was leveled to that of B16 tumors. CD62E is revealed as an angiogenic factor. Less

白细胞介素12（IL-12）在不同的模型中被证明能诱导有效的抗肿瘤和抗转移免疫应答。有研究表明IL-12具有抗血管生成作用。本研究的目的是利用活体显微镜系统阐明IL-12对人胰腺癌血管生成的抑制作用。我们使用严重联合免疫缺陷小鼠（SCID）。皮褶腔模型用于评估PK-1（胰腺癌细胞）或IL-12基因工程PK-1（IL-12/PK-1）植入后的肿瘤生长和血管生成。通过活体显微镜记录新生血管的图像并离线分析。研究抗IFN γ和抗IL-12抗体的作用。注射抗去唾液酸GM 1抗体阻断天然免疫。虽然没有注射去唾液酸GMI抗体来阻断PK-1和IL-12/PK-1在体外生长曲线上的天然免疫差异，但IL-12/PK-1的生长受到显著抑制 ...更多信息 与体内PK-1相比。皮褶室实验显示IL-12/PL-1对肿瘤血管生成有较强的抑制作用。IL-12抗体施用允许IL-12/PK-1植入后肿瘤发展。研究表明，IL-12的抗血管生成作用阻止了胰腺癌的生长。IL-12局部给药系统有望成为胰腺癌治疗的新策略，表达于内皮细胞表面的CD 62 E（B-selectin，SLAM，1）可与肿瘤细胞表面的配体sLeas和sLex结合。还发现可溶形式的E-选择素促进炎症和肿瘤血管生成。为探讨CD 62 E在肿瘤微环境中的作用。我们从小鼠C-26结肠腺癌细胞系中分离了CD 62 B cDNA，我们通过FACScan发现该细胞系表达CD 62 B。将CD 62 E cDNA转染至不表达CD 62 B的小鼠黑色素瘤细胞系B16（B 16/B）中。当肿瘤在SCID小鼠的透明腔中生长时，B16/E肿瘤比通过快速新生血管形成而被抑制的B16肿瘤生长得更快。用一种新合成的选择性拮抗剂KB-R9188（10 mg/kg）腹腔注射给SCID小鼠，连续20天后，B16/B肿瘤的生长与B16肿瘤的生长持平。CD 62 E是一种血管生成因子。少

项目成果

Lozonschi L., Sunamaura M.: "How can fractal analysis help underatanding tumor angiogenesis?" Microcirculation annual. 13. 19-20 (1997)

Lozonschi L.，Sunamaura M.：“分形分析如何帮助了解肿瘤血管生成？”