Factor VII light chain-targeted lidamycin targets tissue factor-overexpressing tumor cells for cancer therapy.
Factor VII light chain-targeted lidamycin targets tissue factor-overexpressing tumor cells for cancer therapy.
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DOI：
10.3892/ijmm.2011.848
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发表时间：
2011-11
影响因子：
5.4
通讯作者：
Qing Zhang;Xiujun Liu;Li-Tai Hu;D. Liao;Yan-Bo Zheng;Y. Zhen;Xu Song
中科院分区：
文献类型：
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作者：
Qing Zhang;Xiujun Liu;Li-Tai Hu;D. Liao;Yan-Bo Zheng;Y. Zhen;Xu Song
组织因子在多种肿瘤细胞和临床标本中的高表达使组织因子成为肿瘤治疗的理想靶点。在这里，我们报道了一种可用于癌症治疗的能源化融合蛋白hlFVII-LDP-AE，它由与细胞毒性抗生素力达霉素(LDM，LDP-AE)偶联的人凝血因子VII轻链(HlFVII)组成。HlFVII-LDP-AE与肿瘤细胞上表达的TF具有特异性结合，导致融合蛋白内化，并由LDM结构域诱导细胞毒作用。采用四甲基偶氮唑盐(3-(4，5-dimethylthiazol-2-yl)-2，5-diphenyltetrazolium)比色法和裸鼠移植人肺癌NCI-H292裸鼠模型，观察hLFVII-LDP-AE对肿瘤的治疗作用。HlFVII-LDP-AE可引起NCI-H292细胞染色质凝聚和基因组DNA断裂。在四甲基偶氮唑盐比色法中，hlFVII-LDP-AE的IC50值为0.19 nm。在体内实验中，两次静脉注射0.6 mg/kg的hLFVII-LDP-AE后，肺癌移植瘤的生长速度降至对照组的15%，且小鼠未见过度的体重减轻和炎症反应。这些结果表明，hlFVII-LDP-AE在NCI-H292人肺癌小鼠模型中是有效的和耐受性的，在治疗癌症患者方面具有广泛的临床适用性。
The overexpression of tissue factor (TF) observed in numerous cancer cells and clinical samples of human cancers make TF an ideal target for cancer therapy. Here, we report an energized fusion protein, hlFVII-LDP-AE, which can be used for cancer therapy and is composed of a human Factor VII light chain (hlFVII) conjugated to the cytotoxic antibiotic lidamycin (LDM, LDP-AE). hlFVII-LDP-AE binds with specificity to TF expressed on tumor cells, resulting in internalization of the fusion protein and cytotoxicity induced by the LDM domain. The potential efficacy of hlFVII-LDP-AE for cancer therapy was examined in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and in vivo with a BALB/c nude mouse xenograft model of the human lung cancer line NCI-H292. hlFVII-LDP-AE caused chromatin condensation and cleavage of genomic DNA in NCI-H292 cells. In the MTT assays, the IC50 value of hlFVII- LDP-AE was 0.19 nM. In the in vivo tests, after two intravenous injections of hlFVII-LDP-AE at a dose of 0.6 mg/kg, the growth rate of the lung tumor xenograft was reduced to 15% of the control rate, and there was no excessive loss of body weight and inflammatory response in the mice. These findings suggest that hlFVII-LDP-AE is efficacious and tolerated in the mouse model of NCI-H292 human lung cancer examined and could have broad clinical applicability for treating cancer patients.