An E1B-19 kDa gene deletion mutant adenovirus demonstrates tumor necrosis factor-enhanced cancer selectivity and enhanced oncolytic potency
An E1B-19 kDa gene deletion mutant adenovirus demonstrates tumor necrosis factor-enhanced cancer selectivity and enhanced oncolytic potency
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DOI：
10.1016/j.ymthe.2004.03.017
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发表时间：
2004-06-01
影响因子：
12.4
通讯作者：
Kirn, D
中科院分区：
文献类型：
--
作者：
Liu, TC;Hallden, G;Kirn, D
溶瘤腺病毒有望成为癌症的新治疗平台，但已经确定了局限性，包括有限的传播和效力。腺病毒蛋白E1B-19 kDa是一种Bcl2同源物，可阻断内源性和外源性途径诱导的细胞凋亡，尤其是肿瘤坏死因子介导的细胞死亡。我们证明了E1B-19 kDa基因缺失突变体在体外和体内都具有肿瘤坏死因子增强的肿瘤选择性，这是由于肿瘤细胞凋亡途径中的遗传障碍。此外，与d/1520(又名Onyx-015)和野生型腺病毒相比，该突变体在体外显示出显著增强的病毒传播和抗肿瘤效力。通过瘤内和静脉给药途径，体内显示了显著的抗肿瘤效果。应考虑将E1B-19 kDa缺失作为溶瘤腺病毒的一个特征，以提高其安全性、传播性和有效性。
Oncolytic adenoviruses hold promise as a new treatment platform for cancer, but limitations have been identified, including limited spread and potency. The adenoviral protein E1B-19 kDa is a Bcl-2 homologue that blocks apoptosis induction via the intrinsic and extrinsic pathways, specifically including tumor necrosis factor-mediated cell death. We demonstrate that an E1B-19 kDa gene deletion mutant had tumor necrosis factor-enhanced cancer selectivity, in vitro and in vivo, due to genetic blocks in apoptosis pathways in cancer cells. in addition, this mutant demonstrated significantly enhanced viral spread and antitumoral potency relative to d/1520 (aka Onyx-015) and wild-type adenovirus in vitro. Significant antitumoral efficacy was demonstrated in vivo by intratumoral and intravenous routes of administration. E1B-19 kDa deletion should be considered as a feature of oncolytic adenoviruses to enhance their safety, spread, and efficacy.