Porphyrin analogues as novel antagonists of fibroblast growth factor and vascular endothelial growth factor receptor binding that inhibit endothelial cell proliferation, tumor progression, and metastasis.
Porphyrin analogues as novel antagonists of fibroblast growth factor and vascular endothelial growth factor receptor binding that inhibit endothelial cell proliferation, tumor progression, and metastasis.
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发表时间：
2000-06
期刊：
影响因子：
11.2
通讯作者：
D. Aviezer;Sara Cotton;Magda David;Amit Segev;Nona Khaselev;N. Galili;Zeev Gross;Avner Yayon
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文献类型：
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作者：
D. Aviezer;Sara Cotton;Magda David;Amit Segev;Nona Khaselev;N. Galili;Zeev Gross;Avner Yayon
成纤维细胞生长因子（FGFs）和血管内皮生长因子（VEGF）在肿瘤进展、转移和血管生成的多步骤通路中发挥关键作用。我们已经鉴定出卟啉类似物5,10,15,20-tetrakis(methyl-4-pyridyl)-21H,23H-porphine-tetra -p-tosylate salt (TMPP)，作为FGF2和VEGF受体结合和激活的有效抑制剂。TMPP可以有效抑制可溶性FGF受体1 （FGFR1）与固定在亚微摩尔浓度肝素上的FGF2的结合。在无细胞系统中，TMPP抑制放射性标记的FGF2与FGFR的结合，也抑制基因工程细胞表达FGFR1的结合。此外，TMPP还以剂量依赖性的方式抑制VEGF与其酪氨酸激酶受体的结合。在测量内皮细胞生长、管形成和发芽程度的体外血管生成实验中，TMPP显著降低了fgf2诱导的内皮细胞生长和分化的程度。在Lewis肺癌模型中，接受TMPP的小鼠显示出原发性肿瘤进展和肺转移发展的明显抑制，每天交替注射25微克/克体重的TMPP几乎完全抑制转移表型。最后，新型中位吡啶取代的非对称卟啉，以及一种新型的基于腐蚀的卟啉衍生物，在体外活性增加了50倍，在体内阻断肿瘤进展和转移的功效显著提高。
Fibroblast growth factors (FGFs) and vascular endothelial growth factor (VEGF) play a pivotal role in the multistep pathway of tumor progression, metastasis, and angiogenesis. We have identified a porphyrin analogue, 5,10,15,20-tetrakis(methyl-4-pyridyl)-21H,23H-porphine-tetra -p-tosylate salt (TMPP), as a potent inhibitor of FGF2 and VEGF receptor binding and activation. TMPP demonstrated potent inhibition of binding of soluble FGF receptor 1 (FGFR1) to FGF2 immobilized on heparin at submicromolar concentrations. TMPP inhibits binding of radiolabeled FGF2 to FGFR in a cell-free system as well as to cells genetically engineered to express FGFR1. Furthermore, TMPP also inhibits the binding of VEGF to its tyrosine kinase receptor in a dose-dependent manner. In an in vitro angiogenic assay measuring the extent of endothelial cell growth, tube formation, and sprouting, TMPP dramatically reduced the extent of the FGF2-induced endothelial cell outgrowth and differentiation. In a Lewis lung carcinoma model, mice receiving TMPP showed a marked inhibition of both primary tumor progression and lung metastases development, with nearly total inhibition of the metastatic phenotype upon alternate daily injections of TMPP at 25 microg/g of body mass. Finally, novel meso-pyridylium-substituted, nonsymmetric porphyrins, as well as a novel corrole-based derivative, with >50-fold increase in activity in vitro, had a significantly improved efficacy in blocking tumor progression and metastasis in vivo.