Oncolytic herpes virus with defective ICP6 specifically replicates in quiescent cells with homozygous genetic mutations in p16.
Oncolytic herpes virus with defective ICP6 specifically replicates in quiescent cells with homozygous genetic mutations in p16.
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DOI：
10.1038/onc.2008.53
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发表时间：
2008-07-10
期刊：
影响因子：
8
通讯作者：
Chiocca EA
中科院分区：
文献类型：
--
作者：
Aghi M;Visted T;Depinho RA;Chiocca EA
在治疗恶性神经胶质瘤的临床试验中，溶瘤单纯疱疹病毒（HSV）被认为对肿瘤细胞具有选择性，因为它们的复制在静止细胞中强烈减弱，但在循环细胞中不减弱。认为发生溶瘤选择性是因为病毒ICP 6（编码病毒核糖核苷酸还原酶功能）和/或γ34.5功能的突变分别由哺乳动物核糖核苷酸还原酶和GADD 34（其基因在循环细胞中表达）补充。然而，据估计，只有5-15%的恶性胶质瘤细胞在任何一个时间处于有丝分裂。因此，HSV溶瘤病毒的有效复制可能仅限于肿瘤细胞的亚群，因为在任何一个时间，大多数肿瘤细胞都不会循环。然而，我们报告说，HSV有缺陷的ICP 6功能复制静止培养的小鼠胚胎成纤维细胞从纯合子p16缺失的小鼠。此外，将这种病毒颅内接种到p16−/−小鼠的大脑中提供了病毒复制的证据，而当将病毒注射到野生型小鼠的大脑中时，不会发生病毒复制。这些方法提供了体外和体内证据，证明ICP 6阴性HSV是“分子靶向的”，因为它们在携带特定癌基因缺失的静止肿瘤细胞中复制，与细胞周期状态无关。
Oncolytic herpes simplex viruses (HSVs), in clinical trials for the treatment of malignant gliomas, are assumed to be selective for tumor cells because their replication is strongly attenuated in quiescent cells, but not in cycling cells. Oncolytic selectivity is thought to occur because mutations in viral ICP6 (encoding a viral ribonucleotide reductase function) and/or γ34.5 function are respectively complemented by mammalian ribonucleotide reductase and GADD34, whose genes are expressed in cycling cells. However, it is estimated that only 5–15% of malignant glioma cells are in mitosis at any one time. Therefore, effective replication of HSV oncolytic viruses might be limited to a subpopulation of tumor cells, since at any one time the majority of tumor cells would not be cycling. However, we report that an HSV with defective ICP6 function replicates in quiescent cultured murine embryonic fibroblasts obtained from mice with homozygous p16 deletions. Furthermore, intracranial inoculation of this virus into the brains of p16−/− mice provides evidence of viral replication that does not occur when the virus is injected into the brains of wild-type mice. These approaches provide in vitro and in vivo evidence that ICP6-negative HSVs are ‘molecularly targeted,’ because they replicate in quiescent tumor cells carrying specific oncogene deletions, independent of cell cycle status.
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影响因子：
5.1
作者：
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3.3
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影响因子：
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