Oncolytic adenovirus that overproduces ADP and replicates selectively in tumors due to hTERT promoter-regulated E4 gene expression
Oncolytic adenovirus that overproduces ADP and replicates selectively in tumors due to hTERT promoter-regulated E4 gene expression
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DOI：
10.1038/sj.gt.3302581
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发表时间：
2005-11-01
期刊：
影响因子：
5.1
通讯作者：
Toth, K
中科院分区：
文献类型：
--
作者：
Kuppuswamy, M;Spencer, JF;Toth, K
我们构建了一种新型的溶瘤腺病毒载体，命名为VRX-011，通过用人端粒酶逆转录酶(HTERT)启动子替换野生型AdE4启动子来针对癌细胞进行复制。AdE4转录单元中的基因对Ad复制至关重要；因此，VRX-011只能在hTERT启动子活跃的细胞中有效生长，即在广泛的癌症和永生化细胞中生长，而不是在大多数体细胞中生长。与这些预期一致，VRX-011在所有被检查的癌细胞系中有效复制，而它在各种原代和正常细胞中的生长受到限制。VRX-011过表达ADP(也称为E3-11.6K)，这是一种在感染后期有效地裂解细胞和释放病毒粒子所必需的Ad蛋白。这种过表达增强了细胞间的扩散，并可能显著提高抗肿瘤效果。在裸鼠异种移植模型中，瘤内和静脉注射VRX-011均有效地抑制了人肝癌Hep3B皮下移植瘤的生长。此外，静脉注射VRX-011大大减少了裸鼠播散性肺癌模型中A549人肺癌细胞结节的数量和大小。重要的是，尾静脉注射不同剂量的VRX-011对C57BL/6小鼠的肝脏毒性最小。考虑到它在癌细胞中广泛的裂解复制，它在原代细胞中的减毒表型，它对异种移植的抑制效果，以及它在小鼠肝脏的低毒，VRX-011是一个有希望的候选药物，作为一种抗癌治疗药物。
We have constructed a novel oncolytic adenovirus (Ad) vector, named VRX-011, in which the replication of the vector is targeted to cancer cells by the replacement of the wild-type Ad E4 promoter with the human telomerase reverse transcriptase ( hTERT) promoter. Genes in the Ad E4 transcription unit are essential for Ad replication; therefore, VRX-011 will grow efficiently only in cells in which the hTERT promoter is active, that is, in a wide range of cancer and immortalized cells but not in most somatic cells. Consistent with these expectations, VRX-011 replicated efficiently in all cancer cell lines examined, while its growth was restricted in various primary and normal cells. VRX-011 overexpresses ADP ( also known as E3-11.6K), an Ad protein required for efficient cell lysis and release of virions from cells at late stages of infection. This overexpression enhances cell-to-cell spread and could significantly increase antitumor efficacy. In a xenograft model in nude mice, both intratumoral and intravenous administration of VRX-011 effectively suppressed the growth of subcutaneous Hep3B human liver tumors. Also, intravenous delivery of VRX-011 greatly reduced the number and size of A549 human lung cancer cell nodules in a disseminated lung tumor model in nude mice. Importantly, tail vein administration of different doses of VRX-011 in C57BL/6 mice showed minimal liver toxicity. Considering its broad range of lytic replication in cancer cells, its attenuated phenotype in primary cells, its efficacy in suppressing xenografts, and its low toxicity in mouse liver, VRX-011 is a promising candidate for further evaluation as an anticancer therapeutic.