The oncolytic poxvirus JX-594 selectively replicates in and destroys cancer cells driven by genetic pathways commonly activated in cancers.
The oncolytic poxvirus JX-594 selectively replicates in and destroys cancer cells driven by genetic pathways commonly activated in cancers.
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DOI：
10.1038/mt.2011.276
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发表时间：
2012-04
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溶瘤病毒通常被设计为基于单个基因突变而具有癌症选择性。JX-594是一种胸苷激酶（TK）基因灭活的溶瘤痘苗病毒，表达粒细胞-巨噬细胞集落刺激因子（GM-CSF）和lac-Z转基因，旨在通过复制依赖性细胞溶解和刺激抗肿瘤免疫来破坏癌细胞。JX-594在临床试验中已证明在各种实体癌类型中具有良好的安全性和可重现的肿瘤坏死。然而，负责其癌症选择性的机制尚未得到很好的描述。我们分析了JX-594在三种模型系统中的复制：原代正常细胞和癌细胞、手术外植体和小鼠肿瘤模型。JX-594的复制、转基因表达和细胞病变效应具有高度的癌症选择性，并且证明了广谱活性。JX-594癌症选择性是多机制的;复制被表皮生长因子受体（EGFR）/Ras通路信号传导、细胞TK水平和癌细胞对I型干扰素（IFN）的抗性激活。这些发现证实了JX-594的大治疗指数，这是由人类实体瘤中常见的遗传异常驱动的。这似乎是第一次描述溶瘤病毒的多种选择性机制，包括固有的和工程化的。这些发现对溶瘤病毒具有普遍意义，并表明它们的癌症靶向是一个复杂的多因素过程。
Oncolytic viruses are generally designed to be cancer selective on the basis of a single genetic mutation. JX-594 is a thymidine kinase (TK) gene-inactivated oncolytic vaccinia virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and lac-Z transgenes that is designed to destroy cancer cells through replication-dependent cell lysis and stimulation of antitumoral immunity. JX-594 has demonstrated a favorable safety profile and reproducible tumor necrosis in a variety of solid cancer types in clinical trials. However, the mechanism(s) responsible for its cancer-selectivity have not yet been well described. We analyzed the replication of JX-594 in three model systems: primary normal and cancer cells, surgical explants, and murine tumor models. JX-594 replication, transgene expression, and cytopathic effects were highly cancer-selective, and broad spectrum activity was demonstrated. JX-594 cancer-selectivity was multi-mechanistic; replication was activated by epidermal growth factor receptor (EGFR)/Ras pathway signaling, cellular TK levels, and cancer cell resistance to type-I interferons (IFNs). These findings confirm a large therapeutic index for JX-594 that is driven by common genetic abnormalities in human solid tumors. This appears to be the first description of multiple selectivity mechanisms, both inherent and engineered, for an oncolytic virus. These findings have implications for oncolytic viruses in general, and suggest that their cancer targeting is a complex and multifactorial process.
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DOI：
10.1038/nrmicro1927
发表时间：
2008-07
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
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影响因子：
64.8
作者：
BULLER, RML;SMITH, GL;MOSS, B
通讯作者：
MOSS, B
影响因子：
12.4
作者：
Eramo, A.;Lotti, F.;De Maria, R.
通讯作者：
De Maria, R.
影响因子：
82.9
作者：
Heise, C;Hermiston, T;Kirn, D
通讯作者：
Kirn, D
影响因子：
5.1
作者：
Foloppe, J.;Kintz, J.;Erbs, P.
通讯作者：
Erbs, P.