Inhibition of the alpha-nu integrins with a cyclic RGD peptide impairs angiogenesis, growth and metastasis of solid tumours in vivo.
Inhibition of the alpha-nu integrins with a cyclic RGD peptide impairs angiogenesis, growth and metastasis of solid tumours in vivo.
复制标题
用环状RGD肽抑制α-NU整联蛋白会损害体内实体瘤的血管生成，生长和转移。
DOI：
10.1038/sj.bjc.6600141
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发表时间：
2002-03-04
影响因子：
8.8
通讯作者：
Dellian, M
中科院分区：
文献类型：
--
作者：
Buerkle, M A;Pahernik, S A;Sutter, A;Jonczyk, A;Messmer, K;Dellian, M
抗血管生成癌症治疗是一种潜在的治疗实体肿瘤的新形式。αv-整合素（αvβ3, αvβ5）介导肿瘤血管生成过程中活化的内皮细胞与细胞外基质蛋白的接触，是内皮细胞存活的先决条件。本研究旨在探讨甲基化环rgd肽作为αv整合素拮抗剂对体内实体肿瘤血管生成、微循环、生长和转移形成的影响。实验在携带无黑色素瘤仓鼠黑色素瘤A-Mel-3的叙利亚金仓鼠背部皮肤褶制备中进行。每12 h腹腔注射1个甲基化的环状rgd -肽，对照组注射1个无活性肽。用活体显微镜分析肿瘤血管生成的微循环参数，包括功能血管密度、红细胞速度、血管直径和白细胞-内皮相互作用。在另一项研究中，对皮下A-Mel-3的生长和转移的影响进行了量化。与对照组相比，治疗组动物的功能血管密度在第3天显著降低（37.2±12.1 vs 105.2±11.2 cm−1;mean±s.e.m； P<0.05），随后两组动物的功能血管密度均增加。第3天红细胞速度低于对照组（0.026±0.01 vs 0.12±0.03 mm s−1；P<0.05）。两组血管直径无差异，白细胞-内皮细胞相互作用几乎不存在。此外，与对照组相比，给予环状rgd肽后皮下肿瘤的生长和转移明显延迟（P<0.05）。环rgd -肽抑制αv-整合素可显著降低功能性血管密度，延缓肿瘤生长和转移。综上所述，这些结果表明rgd -肽在体内具有抗肿瘤和抗转移活性。英国癌症杂志（2002）86,788-795。DOI: 10.1038/sj/bjc/6600141 www.bjcancer.com©2002英国癌症研究中心
Anti-angiogenetic cancer therapy is a potential new form for treatment of solid tumours. The αv-integrins (αvβ3, αvβ5) mediate the contact of activated endothelial cells to proteins of the extracellular matrix during tumour angiogenesis as a prerequisite for survival of endothelial cells. The aim of this study was to investigate the effects of application of a methylated cyclic RGD-peptide as an αv-integrin antagonist on angiogenesis, microcirculation, growth and metastasis formation of a solid tumour in vivo. Experiments were performed in the dorsal skinfold preparation of Syrian Golden hamsters bearing the amelanotic hamster melanoma A-Mel-3. Animals were injected intraperitoneally with a methylated cyclic RGD-peptide every 12 h, the control group received an inactive peptide. Microcirculatory parameters of tumour angiogenesis including functional vessel density, red blood cell velocity, vessel diameter and leucocyte–endothelium interaction were analysed using intravital microscopy. In an additional study the effects on growth and metastasis of subcutaneous A-Mel-3 were quantified. Functional vessel density was markedly reduced on day 3 in treated animals compared to controls (37.2±12.1 vs 105.2±11.2 cm−1; mean±s.e.m.; P<0.05) and increased subsequently in both groups. Red blood cell velocity at day 3 was below values of controls (0.026±0.01 vs 0.12±0.03 mm s−1; P<0.05). No differences were observed in vessel diameters and leucocyte–endothelium interaction was almost absent in both groups. Furthermore, growth and metastasis of subcutaneous tumours after administration of the cyclic RGD-peptide was significantly delayed in comparison to controls (P<0.05). Inhibition of αv-integrins by a cyclic RGD-peptide resulted in significant reduction of functional vessel density, retardation of tumour growth and metastasis in vivo. Taken together, these results implicate RGD-peptides as agents which have anti-tumour and anti-metastatic activity in vivo. British Journal of Cancer (2002) 86, 788–795. DOI: 10.1038/sj/bjc/6600141 www.bjcancer.com © 2002 Cancer Research UK