Oncolytic herpes simplex virus mutants are more efficacious than wild-type adenovirus type 5 for the treatment of high-risk neuroblastomas in preclinical models
Oncolytic herpes simplex virus mutants are more efficacious than wild-type adenovirus type 5 for the treatment of high-risk neuroblastomas in preclinical models
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DOI：
10.1002/pbc.20268
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发表时间：
2005-05-01
影响因子：
3.2
通讯作者：
Cripe, TP
中科院分区：
文献类型：
--
作者：
Parikh, NS;Currier, MA;Cripe, TP
背景资料。在大多数患者中，高危神经母细胞瘤(NB)在目前的治疗方案下是无法治愈的。溶瘤病毒疗法是一种新的方法，正在对几种类型的成人癌症进行测试。比较肿瘤模型对溶瘤腺病毒和单纯疱疹病毒变异株的敏感性，阐明耐药或敏感的机制。用腺病毒5型野生型和HSV1突变型(NV1066)感染人NB细胞系，观察腺病毒受体的表达、对NV1066复制的支持和对细胞凋亡的诱导。评价免疫缺陷小鼠的人移植瘤对瘤内注射溶瘤型单纯疱疹病毒变异体的组织学影响和肿瘤反应。在培养中测试的所有8个NB细胞系对野生型腺病毒和减毒型腺病毒感染都具有相对抵抗力。细胞表达蟑螂-腺病毒附着受体(CAR)，但低表达或不表达内化受体(α(V)β(3)、α(V)β(5)整合素)。相比之下，所有细胞对HSV减毒突变株NV1066的感染都一致敏感。在HSV感染的细胞中观察到高效的病毒复制和诱导细胞凋亡。单次注射NV1066的CHLA-20和LAN-5移植瘤显示出显著的抗肿瘤效应，并且与PBS处理的对照组相比，动物在感染后存活时间延长。单纯疱疹病毒注射的肿瘤有广泛的坏死区和细胞凋亡的形态证据。鼻咽癌模型对腺病毒介导的溶瘤作用耐药，但对HSV介导的溶瘤作用高度敏感。HSV病毒疗法作为一种治疗NB的新方法值得进一步研究。(C)2004年Wiley-Liss公司
Background. High-risk neuroblastoma (Nb) is incurable using current treatment regimens in the majority of patients. Oncolytic virotherapy is a novel approach being tested for several types of adult cancers.Objectives. To compare the susceptibility of Nb tumor models to oncolytic adenovirus and HSV mutants and delineate the mechanisms of resistance or sensitivity.Methods. Human Nb cell lines were used to determine susceptibility to adenovirus type 5 wild-type and HSV1 mutant (NV1066) infection, adenovirus receptor expression, support of NV1066 replication, and induction of apoptosis. Human xenograft tumors in immunodeficient mice were evaluated for histological effects and tumor response to intralumoral injection of an oncolytic HSV mutant.Results. All eight Nb cell lines tested in culture were relatively resistant to infection with wild type and attenuated adenoviruses. Cells expressed the cocksackie-adenovirus attachment receptor (CAR) but had low or absent expression of the internalization receptors (alpha(v)beta(3), alpha(v)beta(5) integrins). In contrast, all cells were uniformly sensitive to infection with the attenuated HSV mutant, NV1066. Productive virus replication and induction of apoptosis were observed in HSV-infected cells. CHLA-20 and LAN-5 xenograft tumors injected with a single dose of NV1066 showed a significant antitumor response, and the animals had a prolonged survival post infection in comparison to the PBS-treated control group. HSV injected tumors showed extensive areas of necrosis and morphologic evidence of apoptosis.Conclusions. Nb tumor models are resistant to adenovirus mediated oncolysis but highly sensitive to HSV mediated oncolysis. Further studies of HSV virotherapy as a novel treatment for Nb are warranted. (c) 2004 Wiley-Liss, Inc.