A conditionally replicating adenovirus targeted to tumor cells through activated RAS/P-MAPK-selective mRNA stabilization
A conditionally replicating adenovirus targeted to tumor cells through activated RAS/P-MAPK-selective mRNA stabilization
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DOI：
10.1038/nbt835
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发表时间：
2003-07-01
影响因子：
46.9
通讯作者：
Vile, RG
中科院分区：
文献类型：
--
作者：
Ahmed, A;Thompson, J;Vile, RG
与炎症和/或增殖的快速反应相关的各种蛋白质的表达可以控制在mRNA稳定的水平。由于肿瘤细胞不断重复细胞内的增殖程序，我们使用了肿瘤细胞选择性稳定mRNA作为控制治疗基因表达的一种手段。我们描述了一种有条件复制能力的腺病毒载体，其中必需的腺病毒早期区域1A(E1A)基因的表达通过连接到Ptgs2(也称为COX2)的3个非翻译区(UTR)来调节，Ptgs2是编码前列腺素-过氧化物合酶2的基因，允许激活的RAS/P-MAPK特异性稳定其mRNA。激活的RAS的诱导支持复制，而激活的RAS/P-MAPK不表达的匹配细胞在体外和体内都不利于病毒复制。还需要进一步的肿瘤靶向策略，以防止病毒在通常诱导Ptgs2的肿瘤外部位复制。许多不同的基因包含3个UTRs，它们控制着不同生理、病理和肿瘤相关条件下选择性mRNA的稳定性。因此，在mRNA稳定的水平上产生肿瘤选择性是一种在载体设计中具有广泛应用潜力的策略。
The expression of various proteins associated with rapid responses to inflammation and/or proliferation can be controlled at the level of mRNA stability. Because tumor cells continually recapitulate intracellular programs of proliferation, we have used tumor cell-selective stabilization of mRNA as a means to control therapeutic gene expression. We describe an adenoviral vector that is conditionally replication competent in which expression of the essential adenoviral early region 1A (E1A) gene is regulated by ligation to the 3 untranslated region (UTR) of PTGS2 (also known as COX2), the gene encoding prostaglandin-endoperoxide synthase 2, allowing activated RAS/P-MAPK-specific stabilization of its mRNA. Induction of activated RAS supports replication, whereas matched cells in which activated RAS/P-MAPK is not expressed are very poor substrates for viral replication both in vitro and in vivo. Further tumor-targeting strategies will also be required to prevent viral replication at extratumoral sites where PTGS2 is normally induced. Many different genes contain 3 UTRs that control selective mRNA stability under different physiological, pathological and tumor-associated conditions. Therefore, generating tumor selectivity at the level of mRNA stability is a strategy with broad potential applicability in vector design.