Department of Neuro-oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77035, USA.
Cell Death Dis. 2011 Feb 24;2(2):e121. doi: 10.1038/cddis.2010.95.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in malignant cells, including gliomas, and is currently in anticancer clinical trials. However, the full-length and tagged forms of TRAIL, unlike the untagged ligand (soluble TRAIL (sTRAIL)), exhibits toxicity against normal cells. Here, we report the generation and testing of an adenovirus (AdsTRAIL) that expresses untagged sTRAIL in an intracranial xenograft model and a human glioma organotypic slice culture model. AdsTRAIL efficiently induced apoptosis in glioma cell lines, including those resistant to sTRAIL, but not in normal human astrocytes (NHAs). It inhibited anchorage-independent glioma growth and exerted a bystander effect in transwell assays. Intratumoral injections of AdsTRAIL in a rodent intracranial glioma model resulted in reduced tumor growth and improved survival compared with Ad-enhanced green fluorescent protein (EGFP)- or vehicle-treated controls without toxicity. Human glioma organotypic slices treated with AdsTRAIL demonstrated apoptosis induction and caspase activation.
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）选择性地诱导包括神经胶质瘤在内的恶性细胞凋亡，目前正在进行抗癌临床试验。然而，全长和标记形式的 TRAIL 与未标记的配体（可溶性 TRAIL（sTRAIL））不同，对正常细胞表现出毒性。在这里，我们报告了一种腺病毒（AdsTRAIL）的产生和测试，该腺病毒在颅内异种移植模型和人神经胶质瘤器官型切片培养模型中表达未标记的 sTRAIL。AdsTRAIL 可有效诱导神经胶质瘤细胞系凋亡，包括对 sTRAIL 耐药的细胞系，但对正常人星形胶质细胞（NHAs）没有作用。它抑制了非锚定依赖性神经胶质瘤的生长，并在 Transwell 测定中发挥了旁观者效应。与 Ad-增强型绿色荧光蛋白（EGFP）或载体处理的对照组相比，在啮齿动物颅内神经胶质瘤模型中瘤内注射 AdsTRAIL 可导致肿瘤生长减少和生存率提高，且无毒性。用 AdsTRAIL 处理的人神经胶质瘤器官型切片显示诱导细胞凋亡和半胱氨酸天冬氨酸蛋白酶激活。
