Naumann Ulrike, Waltereit Robert, Schulz Jörg B, Weller Michael
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, School of Medicine, Hoppe-Seyler-Str 3, D-72076 Tübingen, Germany.
J Neurooncol. 2003 Jan;61(1):7-15. doi: 10.1023/a:1021248329980.
Death ligand-mediated apoptosis is a promising strategy of gene therapy for human malignant glioma. We here report that the infection of human malignant glioma cell lines with an adenoviral vector encoding full length human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Ad-Apo2L/TRAIL) results in strong Apo2L/TRAIL transgene expression and the release of full-length Apo2L/TRAIL into the cell culture medium. However, Ad-Apo2L/TRAIL is a poor inducer of cell death, even in the presence of inhibitors of protein synthesis, in human glioma cell lines which are sensitive to soluble recombinant human His-tagged Apo2L/TRAIL (amino acids 114-281). Moreover, Ad-Apo2L/TRAIL gene transfer inhibits soluble His-tagged Apo2L/TRAIL-induced apoptosis, strongly suggesting that the adenovirally encoded full-length Apo2L/TRAIL is not a suitable molecule for glioma cancer gene therapy. This study has important implications for the future development of therapeutic strategies aiming at death receptor activation in refractory cancers such as malignant glioma.
死亡配体介导的细胞凋亡是一种有前景的人类恶性胶质瘤基因治疗策略。我们在此报告，用编码全长人Apo2配体/肿瘤坏死因子相关凋亡诱导配体（Ad-Apo2L/TRAIL）的腺病毒载体感染人类恶性胶质瘤细胞系，会导致Apo2L/TRAIL转基因的强烈表达，并使全长Apo2L/TRAIL释放到细胞培养基中。然而，在对可溶性重组人His标签Apo2L/TRAIL（氨基酸114 - 281）敏感的人类胶质瘤细胞系中，即使存在蛋白质合成抑制剂，Ad-Apo2L/TRAIL也不是细胞死亡的良好诱导剂。此外，Ad-Apo2L/TRAIL基因转移抑制了可溶性His标签Apo2L/TRAIL诱导的细胞凋亡，这强烈表明腺病毒编码的全长Apo2L/TRAIL不是用于胶质瘤癌症基因治疗的合适分子。这项研究对旨在激活难治性癌症（如恶性胶质瘤）中死亡受体的治疗策略的未来发展具有重要意义。
