Potent antitumoral effects of targeted promoter-driven oncolytic adenovirus armed with Dm-dNK for breast cancer in vitro and in vivo
Potent antitumoral effects of targeted promoter-driven oncolytic adenovirus armed with Dm-dNK for breast cancer in vitro and in vivo
复制标题
携带 Dm-dNK 的靶向启动子驱动的溶瘤腺病毒对乳腺癌的体外和体内有效抗肿瘤作用。
DOI：
10.1016/j.canlet.2012.09.003
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发表时间：
2013-01-01
期刊：
影响因子：
9.7
通讯作者：
Zheng, Xinyu
中科院分区：
文献类型：
--
作者：
Dong, Xiaoshen;Qu, Wenzhi;Zheng, Xinyu
目前，没有治愈性治疗可用于晚期转移性或复发性乳腺癌，因为癌症耐受化疗和内分泌治疗。在这项研究中，我们研究了一种具有新型自杀基因的双调节溶瘤腺病毒载体治疗乳腺癌的可行性。在条件复制腺病毒（CRAds）靶向基因病毒治疗后，将新型黑腹果蝇多底物脱氧核苷激酶自杀基因（Dm-DNK）插入双调节溶瘤腺病毒SG 500中，以确保更安全并增强抗乳腺癌的作用体外和体内活性。在几种乳腺细胞系（MDA-MB-231和MCF-7）、正常细胞（WI-38和MRC-5）和人（MDA-MB-231）体内肿瘤模型中研究了选择性复制、细胞杀伤效力和细胞毒性以及与化疗药物的组合。双调节SG 500-dNK在乳腺癌中具有高细胞杀伤活性。在乳腺细胞中复制类似于野生型，在正常细胞中减弱。SG 500-dNK与化疗剂（E）-5-（2-溴乙烯基）-2 '-脱氧尿苷（Bvdu）和2'，2 '-二氟-脱氧胞苷（dFdC）的组合导致协同增强的细胞杀伤，并在体外或体内乳腺异种移植物中大大改善抗肿瘤功效。这些数据表明，新的溶瘤变体SG 500-dNK是一种有前途的候选药物，当与化疗药物联合使用时，可以特异性靶向乳腺肿瘤。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
Currently, no curative treatments are available for late-stage metastatic or recurrent breast cancer, because the cancer tolerates both chemotherapy and endocrine therapy. In this study, we investigated the feasibility of a dual-regulated oncolytic adenoviral vector with a novel suicide gene to treat breast cancer. Following targeted gene virotherapy of conditionally replicating adenoviruses (CRAds), the novel suicide gene of multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster (Dm-DNK) was inserted into the double-regulated oncolytic adenovirus SG500 to ensure more safety and enhanced antitumor activity against breast cancer both in vitro and in vivo. Selective replication, cell-killing efficacy, and cytotoxicity, combined with chemotherapeutics were investigated in several breast cell lines (MDA-MB-231 and MCF-7), normal cells (WI-38 and MRC-5), and human (MDA-MB-231) tumor models in vivo. The double-regulated SG500-dNK had high cell-killing activity in breast cancer. Replication was similar to wild-type in breast cells and was attenuated in normal cells. SG500-dNK combined with the chemotherapeutics (E)-5-(2-bromovinyl)-2'-deoxyuridine (Bvdu) and 2',2'-difluoro-deoxycytidine (dFdC) resulted in synergistically enhanced cell killing and greatly improved antitumor efficacy in vitro or in breast xenografts in vivo. These data suggest that the novel oncolytic variant SG500-dNK is a promising candidate for targeting breast tumors specifically when combined with chemotherapeutics. (C) 2012 Elsevier Ireland Ltd. All rights reserved.