TERT promoter-driven adenovirus vector for cancer gene therapy via systemic injection
TERT promoter-driven adenovirus vector for cancer gene therapy via systemic injection
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DOI：
10.1016/j.bbrc.2007.08.001
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发表时间：
2007-10-19
影响因子：
3.1
通讯作者：
Nakagawa, Shinsaku
中科院分区：
文献类型：
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作者：
Yao, Xinglei;Yoshioka, Yasuo;Nakagawa, Shinsaku
腺病毒载体在肿瘤基因治疗研究中得到了广泛的应用。然而，Adv的临床应用目前仅限于局部、肿瘤内给药；全身给药可导致肝脏中转基因基因的冗余表达和随后的肝毒性。在这里，我们用肿瘤特异性端粒逆转录酶（TERT）启动子取代了Adv的传统巨细胞病毒（CMV）启动子，以限制Adv转导的转基因仅在肿瘤组织中的表达。我们评估了在携带甲氧嘧啶肿瘤的小鼠中全身给予表达单纯疱疹病毒胸苷激酶（Ad-HSVtk）的Adv的治疗效果和副作用。虽然全身注射CNIV启动子驱动的Ad-HSVtk缺乏治疗效果，但注射含有TERT启动子驱动的Ad-HSVtk的2 x 10 11病毒颗粒的小鼠显示出抑制肿瘤生长和延长生存期的副作用最小。我们的研究结果表明，由TERT启动子驱动的转基因表达的Adv是一种有希望的肿瘤靶向载体的原型，可用于有效和安全的癌症基因治疗。(c) 2007爱思唯尔公司版权所有。
Adenovirus vectors (Adv) are used widely in cancer gene therapy research. However, the clinical application of Adv currently is limited to local, intratumoral administration; systemic administration leads to redundant transgene expression in the liver and subsequent hepatotoxicity. Here we replaced the conventional cytomegalovirus (CMV) promoter of Adv with a tumor-specific telomere reverse transcriptase (TERT) promoter, to restrict expression of the Adv-transduced transgene to tumor tissue alone. We evaluated the therapeutic and side effects after systemic administration of Adv expressing herpes simplex virus thymidine kinase (Ad-HSVtk) in mice bearing Meth-A tumors. Although systemically injected CNIV promoter-driven Ad-HSVtk lacked therapeutic effect, mice injected with 2 x 10 11 viral particles containing TERT promoter-driven Ad-HSVtk showed inhibited tumor growth and prolonged survival with minimal side effects. Our results suggest that Adv in which transgene expression is driven by the TERT promoter are a promising prototype of tumor-targeting vectors for effective and safe cancer gene therapy. (c) 2007 Elsevier Inc. All rights reserved.