A Fiber Chimeric CRAd Vector Ad5/11-D24 Double-Armed with TRAIL and Arresten for Enhanced Glioblastoma Therapy
A Fiber Chimeric CRAd Vector Ad5/11-D24 Double-Armed with TRAIL and Arresten for Enhanced Glioblastoma Therapy
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纤维嵌合 CRAd 载体 Ad5/11-D24 双臂与 TRAIL 和逮捕用于增强胶质母细胞瘤治疗。
DOI：
10.1089/hum.2011.130
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发表时间：
2012-06-01
影响因子：
4.2
通讯作者：
Xia, Haibin
中科院分区：
文献类型：
--
作者：
Li, Xing;Mao, Qinwen;Xia, Haibin
尽管化疗和手术技术的进步，恶性胶质瘤仍然难以治疗。连续复制型腺病毒载体（CRAd）可在肿瘤细胞内选择性复制并杀伤肿瘤细胞，为肿瘤治疗提供了一种新的策略。尽管在CR2的E1区中具有24-bp缺失的CRAd（CRAd 5-D24）已经显示出比其他类型的CRAd载体具有更好的治疗效果，但是目前的CRAd 5-D24对于胶质瘤的有效治疗仍然存在一些缺点。在本研究中，我们首次通过以下策略开发了新型载体CRAd5/11-D24.TRAIL/arresten：（1）用Ad 5/11嵌合纤维修饰CRAd5-D24，以提高其对胶质母细胞瘤的感染效率;和（2）将两个转基因表达盒分别插入E3区域和纤维与E4之间的区域，以增强治疗效果。结果表明，CRAd5/11-D24.TRAIL/arresten对裸鼠胶质瘤生长几乎完全抑制，可能是通过增加抗血管生成和促进肿瘤凋亡。该载体是首次报道的E1A D24缺失、Ad5/11嵌合和双臂溶瘤病毒，与常规溶瘤病毒相比显示出显著改善的抗肿瘤活性。这种新型抗肿瘤药物应在未来的临床前和临床研究中进一步评估。
Malignant gliomas remain refractory to treatment despite advances in chemotherapy and surgical techniques. Conditionally replicating adenoviral vector (CRAd) could kill the tumor cells by selectively replicating in neoplastic cells, which represents a novel strategy for tumor therapy. Although CRAd with a 24-bp deletion in CR2 of the E1 region (CRAd5-D24) has been shown to have a better therapeutic effect over the other types of CRAd vectors, the current CRAd5-D24 still has some shortcomings for an efficient therapy of gliomas. In this study, we developed for the first time a novel vector CRAd5/11-D24.TRAIL/arresten by the following strategies: (1) modify CRAd5-D24 with Ad5/11 chimeric fiber to improve its infection efficiency for glioblastoma; and (2) insert two transgene expression cassettes into the E3 region and the region between the fiber and E4, respectively, for an enhanced therapeutic effect. The results indicated that the CRAd5/11-D24.TRAIL/arresten achieved nearly complete inhibition of glioma growth in nude mice possibly by increased antiangiogenesis and enhanced tumor apoptosis. The vector is the first reported E1A D24-deleted, Ad5/11 chimeric, and dual-armed oncolytic virus that shows markedly improved antitumor activities compared with the conventional oncolytic viruses. This novel antitumor agent should be evaluated further in future preclinical and clinical studies.