Parvovirus H1 selectively induces cytotoxic effects on human neuroblastoma cells
Parvovirus H1 selectively induces cytotoxic effects on human neuroblastoma cells
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DOI：
10.1002/ijc.25168
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发表时间：
2010-09-01
影响因子：
6.4
通讯作者：
Witt, Olaf
中科院分区：
文献类型：
--
作者：
Lacroix, Jeannine;Leuchs, Barbara;Witt, Olaf
尽管采用多模式治疗理念，晚期局部高危神经母细胞瘤仍然是治疗挑战，长期生存率低于 50%。因此，迫切需要治疗神经母细胞瘤的新方法，例如溶瘤病毒疗法。 H-1PV 是一种啮齿动物细小病毒，对受感染的成年动物没有相关致病作用。相反，该病毒具有溶瘤特性，并且对于包括人类来源的细胞在内的各种物种的转化细胞或肿瘤衍生细胞具有特别的细胞毒性。在这里，对溶瘤 H-1PV 用于治疗神经母细胞瘤细胞的应用进行了临床前体外评估。在具有不同 MYCN 状态的 11 种神经母细胞瘤细胞系中分析了 H-1PV 的感染效率、病毒复制和裂解活性。通过感染不同来源的非恶性婴儿细胞的短期培养物证实了病毒的肿瘤选择性。在这些非转化细胞中，没有观察到 H-1PV 对细胞活力或形态的影响。相比之下，在 MOI 为 0.001 至 10 pfu/细胞之间检查的所有神经母细胞瘤细胞系中均诱导了裂解性感染。 H-1PV 活跃复制，感染后 48-96 小时内病毒滴度增加至 5,000 倍。观察到 H-1PV 的裂解作用与 MYCN 癌基因扩增或分化状态无关。此外，还可以证明显着的 G2 阻滞和细胞凋亡的诱导。感染效率高、病毒复制速度快、对神经母细胞瘤细胞具有彻底的溶解作用，再加上 H-1PV 对非转化细胞的低毒性，使这种细小病毒成为神经母细胞瘤溶瘤病毒治疗的有希望的候选者。
Despite multimodal therapeutic concepts, advanced localized and high-risk neuroblastoma remains a therapeutic challenge with a long-term survival rate below 50%. Consequently, new modalities for the treatment of neuroblastoma, e.g., oncolytic virotherapy are urgently required. H-1PV is a rodent parvovirus devoid of relevant pathogenic effects in infected adult animals. In contrast, the virus has oncolytic properties and is particularly cytotoxic for transformed or tumor-derived cells of various species including cells of human origin. Here, a preclinical in vitro assessment of the application of oncolytic H-1PV for the treatment of neuroblastoma cells was performed. Infection efficiency, viral replication and lytic activity of H-1PV were analyzed in 11 neuroblastoma cell lines with different MYCN status. Oncoselectivity of the virus was confirmed by the infection of short term cultures of nonmalignant infant cells of different origin. In these nontransformed cells, no effect of H-1PV on viability or morphology of the cells was observed. In contrast, a lytic infection was induced in all neuroblastoma cell lines examined at MOIs between 0.001 and 10 pfu/cell. H-1PV actively replicated with virus titres increasing up to 5,000-fold within 48-96 hr after infection. The lytic effect of H-1PV was observed independent of MYCN oncogene amplification or differentiation status. Moreover, a significant G2-arrest and induction of apoptosis could be demonstrated. Infection efficiency, rapid virus replication and exhaustive lytic effects on neuroblastoma cells together with the low toxicity of H-1PV for nontransformed cells, render this parvovirus a promising candidate for oncolytic virotherapy of neuroblastoma.