Key Lab of Combined Multi-Organ Transplantation, Institute of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Ministry of Public Health, Hangzhou, People's Republic of China.
Mol Cancer Ther. 2009 May;8(5):1387-97. doi: 10.1158/1535-7163.MCT-08-0962. Epub 2009 May 5.
Conditionally replicating adenoviruses (CRAd) have been under extensive investigations as anticancer agents. Previously, we found that ZD55, an adenovirus serotype 5-based CRAd, infected and killed the leukemia cells expressing coxsackie adenovirus receptor (CAR). However, majority of leukemic cells lack CAR expression on their cell surface, resulting in resistance to CRAd infection. In this study, we showed that SG235, a novel fiber chimeric CRAd that has Ad35 tropism, permitted CAR-independent cell entry, and this in turn produced selective cytopathic effects in a variety of human leukemic cells in vitro and in vivo. Moreover, SG235 expressing exogenous tumor necrosis factor-related apoptosis-inducing ligand (SG235-TRAIL) effectively induced apoptosis of leukemic cells via the activation of extrinsic and intrinsic apoptotic pathway and elicited a superior antileukemia activity compared with SG235. In addition, normal hematopoietic progenitors were resistant to the inhibitory activity of SG235 and SG235-TRAIL. Our data suggest that these novel oncolytic agents may serve as useful tools for the treatment of leukemia.
条件复制型腺病毒（CRAd）作为抗癌药物受到广泛研究。此前，我们发现 ZD55，一种基于腺病毒血清型 5 的 CRAd，能够感染并杀伤表达柯萨奇腺病毒受体（CAR）的白血病细胞。然而，大多数白血病细胞表面缺乏 CAR 表达，导致对 CRAd 感染的抗性。在这项研究中，我们表明，具有 Ad35 嗜性的新型纤维嵌合型 CRAd SG235 允许 CAR 非依赖性细胞进入，进而在体外和体内选择性地杀伤多种人白血病细胞。此外，表达外源性肿瘤坏死因子相关凋亡诱导配体的 SG235（SG235-TRAIL）通过激活外在和内在凋亡途径有效地诱导白血病细胞凋亡，并表现出比 SG235 更优越的抗白血病活性。此外，正常造血祖细胞对 SG235 和 SG235-TRAIL 的抑制活性具有抗性。我们的数据表明，这些新型溶瘤剂可能成为治疗白血病的有用工具。
