In vivo imaging of adenovirus transduction and enhanced therapeutic efficacy of combination therapy with conditionally replicating adenovirus and adenovirus-p27
In vivo imaging of adenovirus transduction and enhanced therapeutic efficacy of combination therapy with conditionally replicating adenovirus and adenovirus-p27
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DOI：
10.1158/0008-5472.can-05-1515
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发表时间：
2006-01-01
期刊：
影响因子：
11.2
通讯作者：
Carbone, DP
中科院分区：
文献类型：
--
作者：
Lee, CT;Lee, YJ;Carbone, DP
基因治疗由于基因转移到肿瘤块的能力差而受到阻碍。我们先前提出了一种组合腺病毒基因治疗，含有表达突变体E1（Delta 24 RGD）的条件复制腺病毒（CRAD）和复制缺陷型E1缺失腺病毒，以提高基因转移的效率。当癌细胞被两种病毒共感染时，由Delta 24 R ⑶表达的突变体El使得复制缺陷型腺病毒能够在肿瘤中复制。在这项研究中，异种移植肿瘤的基因转移率是通过复制缺陷型腺病毒荧光素酶（ad-luc）感染的细胞的生物发光来监测的。用CRAD + ad-luc处理的肿瘤块显示出比ad-luc处理的肿瘤显著更强和更长的荧光素酶表达，并且该表达扩散通过整个肿瘤块而没有显著的全身扩散。用CRAD +复制缺陷型腺病毒-p27转导使p27的表达比单独用ad-p27转导增加24倍。用CRAD +腺病毒-p27处理肺癌细胞系和已建立的肺癌异种移植物也比单独用任一种病毒处理诱导更强的生长抑制。这些发现证实了含有治疗基因的E1缺失腺病毒的选择性复制，这是由于肿瘤中存在由Delta 24 RGD产生的突变E1。此外，这种复制增加了治疗性基因转移率并增强了其抗肿瘤作用。
Gene therapy is hampered by poor gene transfer to the tumor mass. We previously proposed a combination adenoviral gene therapy containing a conditionally replicating adenovirus (CRAD) expressing mutant E1 (Delta 24RGD) and a replication-defective E1-deleted adenovirus to enhance the efficiency of gene transfer. Mutant El expressed by Delta 24RGD enables the replication of replication-defective adenoviruses in tumors when cancer cells are co-infected with both viruses. In this study, gene transfer rates in xenografts tumors were monitored by bioluminescence in cells infected with the replication-defective adenovirus-luciferase (ad-luc). Tumor masses treated with CRAD + ad-luc showed dramatically stronger and more prolonged luciferase expression than ad-luc-treated tumors and this expression spread through the entire tumor mass without significant systemic spread. Transduction with CRAD + replication-defective adenovirus-p27 increased the expression of p27 by 24-fold versus transduction with ad-p27 alone. Treatment of a lung cancer cell line and of established lung cancer xenografts with CRAD + adenovirus-p27 also induced stronger growth suppression than treatment with either virus alone. These findings confirm the selective replication of E1deleted adenovirus containing a therapeutic gene due to the presence of mutant El produced by Delta 24RGD in tumors. Moreover, this replication increased the therapeutic gene transfer rate and enhanced its antitumor effects.