Arora N, Masood R, Zheng T, Cai J, Smith D L, Gill P S
Centre for Biochemical Technology, Delhi, India.
Cancer Res. 1999 Jan 1;59(1):183-8.
Angiogenesis is a critical step in a benign tumor's evolution toward malignancy and metastasis. Tumor cells acquire such a phenotype by their ability to secrete angiogenic factors such as vascular endothelial growth factor (VEGF). VEGF receptors (VEGFRs) flt-1/VEGFR-1 and Flk-1/ KDR/VEGFR-2 are restricted to activated endothelial cells, with the highest expression being in the tumor vasculature. The present study was undertaken to target the VEGFRs. Targeted toxins were developed by recombinant methods by fusing VEGF165 or VEGF121 to the diphtheria toxin (DT) translocation and enzymatic domain (DT390-VEGF165 or DT390-VEGF121). Both fusion proteins were found to be highly toxic to proliferating endothelial cells but not to vascular smooth muscle cells. The fusion protein is also active in Kaposi's sarcoma, a tumor type that expresses high levels of VEGFRs. These fusion proteins completely inhibit the basic fibroblast growth factor-induced growth of new blood vessels in the chick chorioallantoic membrane assay. Furthermore, the fusion toxin substantially retards the growth of Kaposi's sarcoma tumors in mice. Because nearly all tumors induce local angiogenesis with high VEGFR expression, VEGF-derived toxins may have wide application in cancer therapy.
血管生成是良性肿瘤向恶性肿瘤演变及转移过程中的关键步骤。肿瘤细胞通过分泌血管内皮生长因子（VEGF）等血管生成因子获得这种表型。VEGF受体（VEGFRs）flt-1/VEGFR-1和Flk-1/KDR/VEGFR-2仅限于活化的内皮细胞，在肿瘤血管系统中表达最高。本研究旨在靶向VEGFRs。通过重组方法将VEGF165或VEGF121与白喉毒素（DT）的易位和酶结构域融合，开发出靶向毒素（DT390-VEGF165或DT390-VEGF121）。发现这两种融合蛋白对增殖的内皮细胞具有高毒性，但对血管平滑肌细胞无毒性。该融合蛋白在卡波西肉瘤（一种高表达VEGFRs的肿瘤类型）中也具有活性。在鸡胚绒毛尿囊膜试验中，这些融合蛋白完全抑制碱性成纤维细胞生长因子诱导的新血管生长。此外，融合毒素可显著延缓小鼠卡波西肉瘤肿瘤的生长。由于几乎所有肿瘤都会诱导局部血管生成并高表达VEGFRs，VEGF衍生毒素可能在癌症治疗中具有广泛应用。
