Intravenous injection of oncolytic picornavirus SVV-001 prolongs animal survival in a panel of primary tumorbased orthotopic xenograft mouse models of pediatric glioma
Intravenous injection of oncolytic picornavirus SVV-001 prolongs animal survival in a panel of primary tumorbased orthotopic xenograft mouse models of pediatric glioma
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DOI：
10.1093/neuonc/not065
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发表时间：
2013-09-01
期刊：
影响因子：
15.9
通讯作者：
Li, Xiao-Nan
中科院分区：
文献类型：
--
作者：
Liu, Zhigang;Zhao, Xiumei;Li, Xiao-Nan
塞内卡谷病毒（SVV-001）是一种非致病性溶瘤病毒，可全身给药并可穿过血脑屏障。我们检查了其在儿童恶性胶质瘤中的治疗效果和肿瘤细胞感染的机制。在来自6个患者肿瘤原位异种移植小鼠模型（1个间变性星形细胞瘤和5个GBM）的原代培养物、预形成的神经球和自我更新的神经胶质瘤细胞中检查了体外抗肿瘤活性。通过对 3 个许可模型和 2 个耐药模型中预先形成的异种移植物进行系统治疗来检查体内治疗效果。使用神经氨酸酶和凝集素来研究唾液酸在介导 SVV-001 感染中的功能作用，这些酶和凝集素可裂解或竞争性结合连锁特异性唾液酸。SVV-001 在 0.5 至 25 的感染复数下复制并有效杀死原代培养物、预形成的神经球和源自 6 个细胞中的 4 个的自我更新干细胞样单个神经胶质瘤细胞 体外神经胶质瘤模型。单次静脉注射注射 SVV-001（5·10(12) 病毒颗粒/kg）导致原位异种移植物感染，而不损害正常小鼠脑细胞，从而导致所有 3 个许可型和 1 个耐药型小鼠模型的存活时间显着延长（P < .05）。使用神经氨酸酶治疗和使用对 2,3-连接和/或 2,6-连接唾液酸具有特异性的凝集素进行竞争性结合可显着抑制 SVV-001 的感染性 (P < 0.01)。SVV-001 对儿童恶性神经胶质瘤具有很强的抗肿瘤活性，并利用 2,3-连接和 2,6-连接唾液酸作为肿瘤细胞感染的介质。我们的研究结果支持考虑将 SVV-001 用于恶性胶质瘤儿童的临床试验。
Seneca Valley virus (SVV-001) is a nonpathogenic oncolytic virus that can be systemically administered and can pass through the bloodbrain barrier. We examined its therapeutic efficacy and the mechanism of tumor cell infection in pediatric malignant gliomas.In vitro antitumor activities were examined in primary cultures, preformed neurospheres, and self-renewing glioma cells derived from 6 patient tumor orthotopic xenograft mouse models (1 anaplastic astrocytoma and 5 GBM). In vivo therapeutic efficacy was examined by systemic treatment of preformed xenografts in 3 permissive and 2 resistant models. The functional role of sialic acid in mediating SVV-001 infection was investigated using neuraminidase and lectins that cleave or competitively bind to linkage-specific sialic acids.SVV-001 at a multiplicity of infection of 0.5 to 25 replicated in and effectively killed primary cultures, preformed neurospheres, and self-renewing stemlike single glioma cells derived from 4 of the 6 glioma models in vitro. A single i.v. injection of SVV-001 (5 10(12) viral particles/kg) led to the infection of orthotopic xenografts without harming normal mouse brain cells, resulting in significantly prolonged survival in all 3 permissive and 1 resistant mouse models (P .05). Treatment with neuraminidase and competitive binding using lectins specific for 2,3-linked and/or 2,6-linked sialic acid significantly suppressed SVV-001 infectivity (P .01).SVV-001 possesses strong antitumor activity against pediatric malignant gliomas and utilizes 2,3-linked and 2,6-linked sialic acids as mediators of tumor cell infection. Our findings support the consideration of SVV-001 for clinical trials in children with malignant glioma.