Treatment of experimental glioma by administration of adenoviral vectors expressing Fas ligand
Treatment of experimental glioma by administration of adenoviral vectors expressing Fas ligand
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DOI：
10.1089/10430349950017644
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发表时间：
1999-07-01
影响因子：
4.2
通讯作者：
Fontana, A
中科院分区：
文献类型：
--
作者：
Ambar, BB;Frei, K;Fontana, A
Fas配体（FasL）是由活化的T细胞和NK细胞产生的细胞因子，其触发包括人脑胶质瘤细胞的Fas阳性靶细胞的凋亡。如本文所示，在体外用表达在巨细胞病毒启动子控制下的Fast cDNA的重组腺病毒（rAd）（rAd-CMV-FasL）感染大鼠F98和人LN 18胶质瘤细胞系，在Fas阳性胶质瘤细胞系中诱导显著的细胞毒性，但在Fas阴性F98胶质瘤亚系F98/ZH中不诱导。Fast介导的细胞毒性作用的程度超出了基于表达lacZ基因的对照病毒（rAd-CMV-lacZ）感染的F98细胞的β-半乳糖苷酶（β-Gal）表达的预期。检测感染细胞上清液中的FasL生物活性提供了涉及Fast对未感染细胞的细胞毒性作用的旁观者机制的证据。在F98荷瘤大鼠中，与rAd-CMV-lacZ感染或未处理的对照组相比，rAd-CMV-FasL感染使平均生存时间增加50%。这些数据表明，病毒载体转导的快速基因可能是一个成功的神经胶质瘤基因治疗的一部分。
Fas ligand (FasL) is a cytokine, produced by activated T cells and NK cells, that triggers apoptosis of Fas-positive target cells including human glioma cells. As shown here, in vitro infection of rat F98 and human LN18 glioma cell lines with recombinant adenovirus (rAd) expressing Fast cDNA under control of the cytomegalovirus promoter (rAd-CMV-FasL) induced striking cytotoxicity in Fas-positive glioma cell lines but not in the Fas-negative F98 glioma subline F98/ZH. The extent of Fast-mediated cytotoxic effects outranged the expectations based on expression of beta-galactosidase (beta-Gal) by F98 cells infected with a control virus expressing the lacZ gene (rAd-CMV-lacZ), The detection of FasL bioactivity in supernatants of infected cells provides evidence of a bystander mechanism involving the cytotoxic action of Fast on uninfected cells. In F98 tumor-bearing rats, infection with rAd-CMV-FasL increased the mean survival time by 50% compared with infection with rAd-CMV-lacZ or untreated controls. These data suggest that viral vector transduction of the Fast gene could be part of a successful glioma gene therapy.