The enhanced tumor selectivity of an oncolytic vaccinia lacking the host range and antiapoptosis genes SPI-1 and SPI-2
The enhanced tumor selectivity of an oncolytic vaccinia lacking the host range and antiapoptosis genes SPI-1 and SPI-2
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DOI：
10.1158/0008-5472.can-05-1630
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发表时间：
2005-11-01
期刊：
影响因子：
11.2
通讯作者：
Bartlett, DL
中科院分区：
文献类型：
--
作者：
Guo, ZS;Naik, A;Bartlett, DL
与正常细胞相比，癌细胞逃避凋亡的能力可能允许缺乏抗凋亡基因的重组牛痘在癌细胞中存活。我们已经探讨了两个牛痘病毒宿主范围/抗凋亡基因，SPI-1和SPI-2的缺失，其对病毒复制的影响和它们在体外感染的正常和转化细胞中诱导细胞死亡的能力。事实上，在三种配对的正常和转化细胞类型中，与正常对应物相比，SPI-1和SPI-2基因缺失病毒（vSP）优先在转化细胞或p53缺失细胞中复制。这种选择性可能来自这样一个事实，即vSP感染的正常细胞比感染的癌细胞死亡更快。一部分感染的细胞死亡，坏死的证据表明，通过流式细胞术和检测的高迁移率B1族蛋白从坏死细胞释放到培养上清液中。当给予动物时，vSP保留在肿瘤组织中复制的全部能力，而在正常组织中的复制大大减少。在病毒发病机制的模型中，与野生型病毒治疗的小鼠相比，vSP治疗的小鼠存活时间更长。突变病毒vSP在MC 38皮下注射中显示出显著的抗肿瘤作用。在裸鼠和免疫活性小鼠肿瘤模型中，P < 0.001和P < 0.05。我们的结论是，这种重组牛痘vSP显示出溶瘤病毒治疗的前景。鉴于其增强的肿瘤选择性，改善的安全性，以及在小鼠模型中全身递送后的实质性溶瘤作用，它也应该作为肿瘤定向基因治疗的有用载体。
The ability of cancer cells to evade apoptosis may permit survival of a recombinant vaccinia lacking antiapoptotic genes in cancer cells compared with normal cells. We have explored the deletion of two vaccinia virus host range/ antiapoptosis genes, SPI-1 and SPI-2, for their effects on the viral replication and their ability to induce cell death in infected normal and transformed cells in vitro. Indeed, in three paired normal and transformed cell types, the SPI-1 and SPI-2 gene-deleted virus (vSP) preferentially replicates in transformed cells or p53-null cells when compared with their normal counterparts. This selectivity may be derived from the fact that vSP-infected normal cells died faster than infected cancer cells. A fraction of infected cells died with evidence of necrosis as shown by both flow cytometry and detection of high-mobility group B1 protein released from necrotic cells into the culture supernatant. When administered to animals, vSP retains full ability to replicate in tumor tissues, whereas replication in normal tissues is greatly diminished. In a model of viral pathogenesis, mice treated with vSP survived substantially longer when compared with mice treated with the wild-type virus. The mutant virus vSP displayed significant antitumoral effects in an MC38 s.c. tumor model in both nude (P < 0.001) and immunocompetent mice (P < 0.05). We conclude that this recombinant vaccinia vSP shows promise for oncolytic virus therapy. Given its enhanced tumor selectivity, improved safety profile, and substantial oncolytic effects following systemic delivery in murine models, it should also serve as a useful vector for tumor-directed gene therapy.