TARGETED INHIBITION OF TUMOR-CELL GROWTH BY RECOMBINANT HEREGULIN-TOXIN FUSION PROTEINS
TARGETED INHIBITION OF TUMOR-CELL GROWTH BY RECOMBINANT HEREGULIN-TOXIN FUSION PROTEINS
复制标题
DOI：
10.1002/ijc.2910600527
复制
发表时间：
1995-03-03
影响因子：
6.4
通讯作者：
GRONER, B
中科院分区：
文献类型：
--
作者：
JESCHKE, M;WELS, W;GRONER, B
通过基因片段的体外重组实现蛋白质功能域的融合可用于产生新型抗肿瘤剂。肿瘤细胞识别功能和毒性功能的结合产生了对肿瘤细胞具有高度特异性的细胞毒性分子。与正常细胞相比，人类腺癌的特征通常是表皮生长因子 (EGF) 受体家族成员（ErbB-1、2、3 和 4）的过度表达。这些肿瘤特别适合用重组毒素治疗。人调蛋白 (HRG) 及其大鼠对应物（神经分化因子，NDF）已被确定为这些受体的配体。构建了两个嵌合调蛋白-毒素融合体，其由调蛋白亚型 HRG α 和 HRG β(1) 的 EGF 样受体识别结构域以及假单胞菌外毒素 A (ETA) 的结构域 II、Ib 和 III 组成。 HRG beta(1)-ETA 对乳腺癌细胞系 SK-BR-3 和 MDA-MB-453 具有高度细胞毒性。 HRG α-ETA 的活性低于 HRG beta(1)-ETA。重组毒素的杀伤活性与所研究的细胞系中ErbB-3和/或ErbB-4的表达水平相关。 ErbB-2 的高表达不足以赋予对 HRG-ETA 的敏感性。用 0.4 mg/kg/天的 HRG beta(1)-ETA 治疗小鼠会导致移植的人乳腺肿瘤细胞生长迟缓。较高水平的 HRG beta(1)-ETA 给药会导致肝脏急性出血性坏死。 (C) 1995 Wiley-Liss, Inc.
Fusion of functional domains of proteins by in vitro recombination of gene fragments can be used to generate novel anti-tumor agents. The combination of tumor-cell-recognition functions and toxic functions results in cytotoxic molecules with a high specificity for tumor cells. Human adenocarcinomas are frequently characterized by over-expression of members of the epidermal-growth-factor (EGF) receptor family (ErbB-1, 2, 3 and 4), when compared with normal cells. These tumors are particularly suited to treatment with recombinant toxins. The human heregulins (HRG) and their rat counterparts (neu differentiation factor, NDF) have been identified as ligands for these receptors. Two chimeric heregulin-toxin fusions consisting of the EGF-like receptor recognition domain of the heregulin isoforms HRG alpha and HRG beta(1), and the domains II, Ib and III of the Pseudomonas exotoxin A (ETA) were constructed. HRG beta(1)-ETA is highly cytotoxic for the mammary carcinoma cell lines SK-BR-3 and MDA-MB-453. HRG alpha-ETA was less active than HRG beta(1)-ETA. The killing activity of the recombinant toxins correlated with the expression levels of ErbB-3 and/or ErbB-4 in the cell lines studied. High expression of ErbB-2 is not sufficient to confer sensitivity towards the HRG-ETA. Treatment of mice with 0.4 mg/kg/day of HRG beta(1)-ETA caused growth retardation of transplanted human breast tumor cells. Higher levels of HRG beta(1)-ETA administration resulted in acute hemorrhagic necrosis of the liver. (C) 1995 Wiley-Liss, Inc.