Efficacy and Safety of Doubly-Regulated Vaccinia Virus in a Mouse Xenograft Model of Multiple Myeloma.
Efficacy and Safety of Doubly-Regulated Vaccinia Virus in a Mouse Xenograft Model of Multiple Myeloma.
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DOI：
10.1016/j.omto.2017.07.001
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发表时间：
2017-09-15
期刊：
影响因子：
--
通讯作者：
Tojo A
中科院分区：
文献类型：
--
作者：
Futami M;Sato K;Miyazaki K;Suzuki K;Nakamura T;Tojo A
多发性骨髓瘤是骨髓浆细胞的恶性肿瘤。尽管预后存在差异，但尚未确定治愈方法。痘苗病毒以多种方式感染癌细胞并杀死这些细胞。这些包括直接感染、引发免疫介导的细胞死亡和血管塌陷。痘苗病毒作为抗肿瘤疗法的潜力引起了肿瘤学家的关注。有趣的是，我们的初步实验表明骨髓瘤细胞特别容易受到牛痘病毒的影响。为了利用这种敏感性并使痘苗病毒更具骨髓瘤特异性，我们生成了胸苷激酶缺失的 microRNA (miRNA) 调节的痘苗病毒，其中重要的病毒基因 B5R 受到正常人类细胞 miRNA 的调节。在检查的 miRNA 中，let-7a 在调节病毒传播方面被发现是最可靠的。暴露于不受管制的痘苗病毒会导致骨髓瘤移植的严重联合免疫缺陷（SCID）小鼠死亡；动物死于病毒毒性。相比之下，胸苷激酶缺失的let-7a调控病毒仍定位于骨髓瘤细胞内，引发肿瘤消退并提高总体生存率。总之，胸苷激酶缺失的 let-7a 调节的痘苗病毒对小鼠是安全有效的，值得在人类中进行临床试验。
Multiple myeloma is a malignancy of plasma cells of the bone marrow. Although the prognosis is variable, no curative therapy has been defined. Vaccinia virus infects cancer cells and kills such cells in a variety of ways. These include direct infection, triggering of immunomediated cell death, and vascular collapse. The potential of the vaccinia virus as an anti-tumor therapy has attracted the attention of oncologists. Interestingly, our preliminary experiments revealed that myeloma cells were particularly susceptible to vaccinia virus. To exploit this susceptibility and to render vaccinia more myeloma specific, we generated thymidine-kinase-deleted microRNA (miRNA)-regulated vaccinia viruses in which the essential viral gene B5R was regulated by miRNAs of normal human cells. Of the miRNAs examined, let-7a was found to be the most reliable in terms of regulating viral transmission. Exposure to unregulated vaccinia virus killed myeloma-transplanted severe combined immunodeficiency (SCID) mice; the animals succumbed to viral toxicity. In contrast, the thymidine-kinase-deleted let-7a-regulated virus remained localized within myeloma cells, triggering tumor regression and improving overall survival. In conclusion, a thymidine-kinase-deleted let-7a-regulated vaccinia virus was safe and effective for mice, warranting clinical trials in humans.
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影响因子：
64.8
作者：
BULLER, RML;SMITH, GL;MOSS, B
通讯作者：
MOSS, B
影响因子：
4.1
作者：
Andrade, AA;Silva, PNG;Bonjardim, CA
通讯作者：
Bonjardim, CA
影响因子：
5.5
作者：
Kenner J;Cameron F;Empig C;Jobes DV;Gurwith M
通讯作者：
Gurwith M
影响因子：
120.7
作者：
Casey, CG;Iskander, JK;Mootrey, G
通讯作者：
Mootrey, G
DOI：
10.1073/pnas.0909376106
发表时间：
2009-10-13
影响因子：
11.1
作者：
Laliberte, Jason P.;Moss, Bernard
通讯作者：
Moss, Bernard