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表达人 TRAIL 的重组安第斯毒株新城疫病毒对荷胶质瘤裸鼠模型具有抗肿瘤作用。

The recombinant Newcastle disease virus Anhinga strain expressing human TRAIL exhibit antitumor effects on a glioma nude mice model.

机构信息

College of Life Science, Northeast Agricultural University, Harbin, Heilongjiang, China.

School of Life sciences & Basic Medicine, Xinxiang University, Xinxiang, Henan, China.

出版信息

J Med Virol. 2021 Jun;93(6):3890-3898. doi: 10.1002/jmv.26419. Epub 2020 Sep 28.

Abstract

Oncolytic virus therapy is perhaps the next major breakthrough in cancer treatment following the success in immunotherapy using immune checkpoint inhibitors. However, the potential oncolytic ability of the recombinant newcastle disease virus (NDV) Anhinga strain carried with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has not been fully explored at present. In the present study, the recombinant NDV/Anh-TRAIL that secretes soluble TRAIL was constructed and the experiment results suggested NDV/Anh-TRAIL as a promising candidate for glioma therapy. Growth kinetic and TRAIL secreted quantity of recombinant NDV/Anh-TRAIL virus were measured. Cytotoxic and cell apoptosis were analyzed for its anti-glioma therapy in vitro. Nude mice were used for the in vivo evaluation. Both tumor volume and mice behavior after injection were observed. The recombinant virus replicated with the same kinetics as the parental virus and the highest expression of TRAIL (77.8 ng/L) was found at 48 hours. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole and flow cytometry data revealed that the recombinant NDV/Anh-TRAIL (56.1 ± 8.2%) virus could induce a more severe apoptosis rate, when compared with the NDV wild type (37.2 ± 7.0%) and mock (7.0 ± 1.8%) groups (P < .01), in U251 cells. Furthermore, in the present animal study, the average tumor volume was smaller in the NDV/Anh-TRAIL group (97.21 mm ), when compared with the NDV wild type (205.03 mm , P < .05) and PBS (310.30 mm , P < .01) groups.

摘要

溶瘤病毒治疗可能是继免疫检查点抑制剂免疫疗法成功之后癌症治疗的下一个重大突破。然而,目前尚未充分探索携带肿瘤坏死因子相关凋亡诱导配体(TRAIL)的重组新城疫病毒(NDV)Anhinga 株的潜在溶瘤能力。本研究构建了分泌可溶性 TRAIL 的重组 NDV/Anh-TRAIL,并通过实验结果表明,NDV/Anh-TRAIL 是一种很有前途的治疗神经胶质瘤的候选药物。测量了重组 NDV/Anh-TRAIL 病毒的生长动力学和 TRAIL 的分泌量。分析了其体外抗神经胶质瘤治疗的细胞毒性和细胞凋亡。利用裸鼠进行体内评价。观察注射后肿瘤体积和小鼠行为。重组病毒的复制动力学与亲本病毒相同,在 48 小时时发现 TRAIL 的最高表达(77.8ng/L)。噻唑蓝(MTT)和流式细胞术数据表明,与 NDV 野生型(37.2±7.0%)和空载(7.0±1.8%)组相比,重组 NDV/Anh-TRAIL(56.1±8.2%)病毒能诱导更严重的 U251 细胞凋亡率(P<.01)。此外,在本动物研究中,与 NDV 野生型(205.03mm3,P<.05)和 PBS 组(310.30mm3,P<.01)相比,NDV/Anh-TRAIL 组的平均肿瘤体积更小(97.21mm3)。

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