Novel oncolytic adenovirus selectively targets tumor-associated polo-like kinase 1 and tumor cell viability
Novel oncolytic adenovirus selectively targets tumor-associated polo-like kinase 1 and tumor cell viability
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DOI：
10.1158/1078-0432.ccr-05-1085
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发表时间：
2005-12-01
影响因子：
11.5
通讯作者：
Ma, D
中科院分区：
文献类型：
--
作者：
Zhou, JF;Gao, QL;Ma, D
目的：Polo-like kinase1(PLK1)是一种丝氨酸/苏氨酸蛋白激酶，在多种有丝分裂过程中起重要作用。先前的观察已经证实PLK1是一个有前途的治疗靶点。尽管在概念上很有吸引力，但目前基于PLK1的疗法的效力和特异性仍然有限。我们试图通过构建溶瘤腺病毒来选择性沉默肿瘤细胞中的PLK1，以开发一种新的PLK1靶向策略。实验设计：将两个人工特征工程到一个野生型腺病毒5型(wt-Adv5)基因组中，生成新的溶瘤腺病毒(M1)。首先，M1在E1a区包含27个碱基的缺失，这赋予了有效的溶瘤效果。第二，M1携带一段反义PLK1基因，取代了编码6.7K和gp19K的E3区。在本设计中，M1的肿瘤选择性复制将激活原生腺病毒E3启动子，在肿瘤细胞中优先表达反义PLK1基因，并沉默肿瘤相关PLK1蛋白。结果：M1通过肿瘤分解和PLK1靶向相结合，在体内外显示出强大的抗肿瘤效果。M1联合顺铂全身给药可使80%对顺铂耐药的原位肝癌模型小鼠肿瘤完全消退。结论：PLK1靶向与肿瘤溶解联用具有良好的抗肿瘤效果。目前的发现将有助于发展新的溶瘤腺病毒，普遍适用于广泛的基于分子的治疗。
Purpose: Polo-like kinase 1 (plk1) is a serine/threonine protein kinase essential for multiple mitotic processes. Previous observations have validated plk1 as a promising therapeutic target. Despite being conceptually attractive, the potency and specificity of current plk1-based therapies remain limited. We sought to develop a novel plk1-targeting strategy by constructing an oncolytic adenovirus to selectively silence plk1 in tumor cells.Experimental Design: Two artificial features were engineered into one wild-type adenovirus type 5 (wt-Adv5) genome to generate a new oncolytic adenovirus (M1). First, M1 contains a 27-bp deletion in E1A region, which confers potent, oncolytic efficacy. Second, M1 is armed with a fragment of antisense plk1 cDNA that substitutes the E3 region encoding 6.7 K and gp19K. In this design, tumor-selective replication of M1 would activate the native adenovirus E3 promoters to express the antisense plk1 cDNA preferentially in tumor cells and silence tumor-associated plk1 protein.Results: By virtue of combining oncolysis with plk1 targeting, M1 exhibited potent antitumoral efficacy in vitro and in vivo. Systemic administration of M1 plus cisplatin induced complete tumor regression in 80% of orthotopic hepatic carcinoma model mice that were otherwise resistant to cisplatin and disseminated metastases.Conclusions: Coupling plk1 targeting with oncolysis had shown superior antitumor efficacy. Present findings would benefit the development of novel oncolytic adenoviruses generally applicable to a wide range of molecule-based therapeutics.