Herpes simplex virus type-1(HSV-1) oncolytic and highly fusogenic mutants carrying the NV1020 genomic deletion effectively inhibit primary and metastatic tumors in mice.
Herpes simplex virus type-1(HSV-1) oncolytic and highly fusogenic mutants carrying the NV1020 genomic deletion effectively inhibit primary and metastatic tumors in mice.
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DOI：
10.1186/1743-422x-5-68
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发表时间：
2008-06-02
期刊：
影响因子：
4.8
通讯作者：
Kousoulas KG
中科院分区：
文献类型：
--
作者：
Israyelyan A;Chouljenko VN;Baghian A;David AT;Kearney MT;Kousoulas KG
NV 1020溶瘤性单纯疱疹病毒1型在实验动物模型和人体试验中显示出治疗许多不同类型肿瘤的显著前景。之前，我们描述了NV 1020样病毒OncSyn的构建和使用，以治疗裸鼠中植入的人乳腺肿瘤。在大肠杆菌中使用双红诱变将合胞体突变gKsyn 1（40位的Ala至瓦尔）引入克隆到细菌人工染色体中的OncSyn病毒基因组中。大肠杆菌中，以产生在gB（syn 3）和gK（syn 1）中携带合胞突变的OncdSyn病毒。OncdSyn病毒在细胞培养物中引起广泛的病毒诱导的细胞融合。在高转移性同基因小鼠模型系统中测试了OncSyn和OncdSyn病毒的溶瘤潜力，该模型系统利用植入Balb/c小鼠肩胛间区域内的4 T1鼠乳腺癌细胞。给小鼠连续三次瘤内注射OncSyn、OncdSyn或磷酸盐缓冲盐水，间隔四天。与对照肿瘤相比，OncSyn和OncdSyn病毒注射均导致肿瘤尺寸显著减小（p < 0.05）。病毒处理的小鼠而非对照组显示肺和内脏中的转移灶显著减少。在整个研究过程中，小鼠体重未受到任何处理的显著影响（p = 0.296）。这些结果表明，减毒但高度融合的OncSyn和OncdSyn病毒可以有效地减少免疫活性小鼠中的原发性和转移性乳腺肿瘤。可用的bac克隆的OncSyn和OncdSyn病毒基因组可以被快速修饰以表达许多不同的抗肿瘤和免疫调节基因，这可以进一步增强它们的抗肿瘤效力。
The NV1020 oncolytic herpes simplex virus type-1 has shown significant promise for the treatment of many different types of tumors in experimental animal models and human trials. Previously, we described the construction and use of the NV1020-like virus OncSyn to treat human breast tumors implanted in nude mice. The syncytial mutation gKsyn1 (Ala-to-Val at position 40) was introduced into the OncSyn viral genome cloned into a bacterial artificial chromosome using double-red mutagenesis in E. coli to produce the OncdSyn virus carrying syncytial mutations in both gB(syn3) and gK(syn1). The OncdSyn virus caused extensive virus-induced cell fusion in cell culture. The oncolytic potential of the OncSyn and OncdSyn viruses was tested in the highly metastatic syngeneic mouse model system, which utilizes 4T1 murine mammary cancer cells implanted within the interscapular region of Balb/c mice. Mice were given three consecutive intratumor injections of OncSyn, OncdSyn, or phosphate buffered saline four days apart. Both OncSyn and OncdSyn virus injections resulted in significant reduction of tumor sizes (p < 0.05) compared to control tumors. Virus treated mice but not controls showed a marked reduction of metastatic foci in lungs and internal organs. Mouse weights were not significantly impacted by any treatment during the course of the entire study (p = 0.296). These results show that the attenuated, but highly fusogenic OncSyn and OncdSyn viruses can effectively reduce primary and metastatic breast tumors in immuncompetent mice. The available bac-cloned OncSyn and OncdSyn viral genomes can be rapidly modified to express a number of different anti-tumor and immunomodulatory genes that can further enhance their anti-tumor potency.