Dual-vector prodrug activator gene therapy using retroviral replicating vectors.
Dual-vector prodrug activator gene therapy using retroviral replicating vectors.
复制标题
DOI：
10.1038/s41417-018-0051-0
复制
发表时间：
2019-05
影响因子：
6.4
通讯作者：
Kasahara N
中科院分区：
文献类型：
--
作者：
Kubo S;Takagi-Kimura M;Tagawa M;Kasahara N
逆转录病毒复制载体（RRV）已被证明可以在多种癌症模型中实现有效的肿瘤转导并增强治疗效果。在本研究中，我们评估了源自双嗜性鼠白血病病毒（AMLV）和长臂猿白血病病毒（GALV）的两种不同RRV传递的前药激活剂基因对人肝细胞癌Hep3B细胞的可能组合效应。两种 RRV 在培养物中均表现出有效的复制传播，并且可以克服彼此的重复感染抗性。值得注意的是，每种 RRV 在培养物中的复制和传播不受对应 RRV 预转导的影响。我们进一步用单独或组合具有前药激活基因酵母胞嘧啶脱氨酶（CD）和单纯疱疹病毒胸苷激酶（TK）的RRV转导细胞，并评估在各自前药5-氟胞嘧啶和更昔洛韦存在下，用CD和TK进行RRV介导的基因治疗的细胞毒性作用。两种前药激活剂基因的所有组合均产生协同杀细胞作用，但当由两种不同载体递送时，不同基因的组合效果显着大于相同基因的组合效果。目前的研究结果表明，使用携带不同前药激活基因的两种不同 RRV 进行双载体基因治疗的潜在效用。
Retroviral replicating vectors (RRVs) have been shown to achieve efficient tumor transduction and enhanced therapeutic benefits in a variety of cancer models. In the present study, we evaluated a possible combinatorial effect of prodrug activator genes delivered by two different RRVs derived from amphotropic murine leukemia virus (AMLV) and gibbon ape leukemia virus (GALV) on human hepatocellular carcinoma Hep3B cells. Both RRVs showed efficient replicative spread in culture and can overcame superinfection resistance each other. Notably, the replication and spread of each RRV in culture remained unaffected by pretransduction with the counterpart RRV. We further transduced cells with RRVs which individually possessed the prodrug activator genes yeast cytosine deaminase (CD) and herpes simplex virus thymidine kinase (TK) alone or in combination, and evaluated the cytotoxic effects of RRV-mediated gene therapy with CD and TK in the presence of the respective prodrugs, 5-fluorocytosine and ganciclovir. All combinations of the two prodrug activator genes produced synergistic cytocidal effects, but the combined effects of the different genes were significantly greater than those of the same genes when delivered by two different vectors. The present findings indicate the potential utility of dual-vector gene therapy using two different RRVs carrying different prodrug activator genes.
登录
查看更多内容
影响因子：
6.4
作者：
Kubo S;Takagi-Kimura M;Logg CR;Kasahara N
通讯作者：
Kasahara N
影响因子：
6.4
作者：
Ichikawa, T;Tamiya, T;Ohmoto, T
通讯作者：
Ohmoto, T
影响因子：
12.4
作者：
Perez, Omar D.;Logg, Christopher R.;Jolly, Douglas J.
通讯作者：
Jolly, Douglas J.
影响因子：
12.4
作者：
Smitt, PS;Driesse, M;Avezaat, C
通讯作者：
Avezaat, C
影响因子：
46.9
作者：
通讯作者：
--