Ambar B B, Frei K, Malipiero U, Morelli A E, Castro M G, Lowenstein P R, Fontana A
Section of Clinical Immunology, University Hospital, Zurich, Switzerland.
Hum Gene Ther. 1999 Jul 1;10(10):1641-8. doi: 10.1089/10430349950017644.
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 FasL 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 FasL-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 FasL 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 FasL gene could be part of a successful glioma gene therapy.
Fas配体（FasL）是一种由活化的T细胞和自然杀伤细胞产生的细胞因子，它能触发包括人胶质瘤细胞在内的Fas阳性靶细胞的凋亡。如本文所示，用在巨细胞病毒启动子控制下表达FasL cDNA的重组腺病毒（rAd）对大鼠F98和人LN18胶质瘤细胞系进行体外感染，可在Fas阳性胶质瘤细胞系中诱导显著的细胞毒性，但在Fas阴性的F98胶质瘤亚系F98/ZH中则无此效应。FasL介导的细胞毒性作用程度超出了基于感染表达lacZ基因的对照病毒（rAd-CMV-lacZ）的F98细胞中β-半乳糖苷酶（β-Gal）表达所预期的范围。在受感染细胞的上清液中检测到FasL生物活性，为涉及FasL对未感染细胞的细胞毒性作用的旁观者机制提供了证据。在荷F98肿瘤的大鼠中，与感染rAd-CMV-lacZ或未治疗的对照组相比，感染rAd-CMV-FasL使平均存活时间延长了50%。这些数据表明，FasL基因的病毒载体转导可能是成功的胶质瘤基因治疗的一部分。
