Synergistic antitumor effect of adenovirus armed with Drosophila melanogaster deoxyribonucleoside kinase and nucleoside analogs for human breast carcinoma in vitro and in vivo.
Synergistic antitumor effect of adenovirus armed with Drosophila melanogaster deoxyribonucleoside kinase and nucleoside analogs for human breast carcinoma in vitro and in vivo.
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携带果蝇脱氧核糖核苷激酶和核苷类似物的腺病毒对人乳腺癌的体外和体内协同抗肿瘤作用。
DOI：
10.2147/dddt.s81717
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Zheng X
中科院分区：
文献类型：
--
作者：
Tang M;Zu C;He A;Wang W;Chen B;Zheng X
癌症自杀基因治疗可以选择性地杀死肿瘤而不损害正常组织。果蝇多底物脱氧核苷激酶（Dm-dNK）是一种原始的自杀激酶，具有更广泛的底物特异性和更高的催化速率，可用于肿瘤自杀基因治疗。为了提高Dm-dNK的抗肿瘤效果，同时保持其底物特异性和安全性，本研究建立了条件复制基因-病毒系统ZD 55-dNK（含有Dm-dNK编码的选择性复制腺病毒ZD 55），以推动该策略的深入发展。将选择性复制、细胞杀伤效力和细胞毒性与化疗组合应用于两种乳腺细胞系（MDA 231和MCF 7细胞）、两种正常细胞系（WI 38和MRC 5细胞）和体内MCF 7异种移植物模型。临床前研究表明，ZD 55-dNK与2′，2 ′-二氟脱氧胞苷（DFDC）联合应用，在体外可协同抑制腺病毒的复制，但仍保持对癌细胞的特异性杀伤作用。ZD 55-dNK在体外和体内对乳腺癌移植瘤的杀伤作用也有显著提高。ZD 55-dNK和DFDC的联合使用可能是一种新的和有前途的乳腺癌治疗方法，需要进一步研究过度病毒复制的安全控制和这种方法在人体中的疗效。
Suicide gene therapy in cancer can selectively kill tumors without damaging normal tissues. Drosophila melanogaster multisubstrate deoxyribonucleoside kinase (Dm-dNK), an original suicide kinase, makes use of the carcinomatous suicide gene therapy for broader substrate specificity and a higher catalytic rate. To enhance the anti-tumor efficacy of Dm-dNK and maintain its substrate specificity and safety control in the meantime, the conditionally replicative gene–viral system, ZD55–dNK (which contains the selective replication adenovirus, ZD55, encoded with Dm-dNK), was investigated in pushing a deeper development of this strategy. Selective replication, cell killing efficacy, and cytotoxicity, in combination with chemotherapy, were applied to two breast cell lines (MDA231 and MCF7 cells), two normal cell lines (WI38 and MRC5 cells), and the MCF7 xenograft model in vivo. The preclinical study showed that ZD55–dNK, combined with 2′,2′-difluorodeoxycytidine (DFDC), synergistically inhibited adenovirus replication in vitro but maintained specifically cancer cell killing efficacy. ZD55–dNK also greatly improved the antineoplastic effect in vitro and in breast cancer xenograft in vivo. The concomitant use of ZD55–dNK and DFDC is possibly a novel and promising approach to breast cancer treatment, and further investigation on the safe control of excessive virus replication and the efficacy of this approach in humans is warranted.