Novel oncolytic agent GLV-1h68 is effective against malignant pleural mesothelioma
Novel oncolytic agent GLV-1h68 is effective against malignant pleural mesothelioma
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DOI：
10.1089/hum.2008.036
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发表时间：
2008-08-01
影响因子：
4.2
通讯作者：
Fong, Yuman
中科院分区：
文献类型：
--
作者：
Kelly, Kaitlyn J.;Woo, Yanghee;Fong, Yuman
恶性胸膜间皮瘤（MPM）是一种致命疾病，中位生存期不到14个月。第一次，基因工程牛痘病毒显示出对MPM产生有效的感染、复制和溶瘤作用。GLV-1h 68是一种可复制的工程化牛痘病毒，携带编码海肾荧光素酶、绿色荧光蛋白（均插入F14.5 L基因座）、β-半乳糖苷酶（插入J2 R基因座，编码胸苷激酶）和β-葡萄糖醛酸酶（插入A56 R基因座，编码血凝素）的转基因。在6种人MPM细胞系（MSTO-211 H、VAMT、JMN、H2373、H-2452和H-2052）中检测了该病毒。GLV-1h 68成功感染所有细胞系。对于最敏感的细胞系MSTO-211 H，绿色荧光蛋白（GFP）的表达在4小时内开始，随着时间的推移强度增加，直到24小时接近100%的细胞表达GFP。当以1.0的感染复数感染时，即使是最具抗性的细胞系在第7天也表现出44 +/-3.8%的细胞存活率。病毒增殖试验表明，在检测的细胞系中，GLV-1h 68的对数复制为2- 4倍。在原位模型中，GLV-1h 68在早期和晚期治疗组中均有效预防恶病质和肿瘤相关发病率的发生，降低肿瘤负荷，并治愈MPM。GLV-1h 68在体外和原位模型（体内）中成功用于治疗MPM。这些有希望的结果证明了GLV-1h 68作为治疗MPM的新型药物的临床研究。
Malignant pleural mesothelioma (MPM) is a fatal disease with a median survival of less than 14 months. For the first time, a genetically engineered vaccinia virus is shown to produce efficient infection, replication, and oncolytic effect against MPM. GLV-1h68 is a replication-competent engineered vaccinia virus carrying transgenes encoding Renilla luciferase, green fluorescent protein (both inserted at the F14.5L locus), beta-galactosidase (inserted at the J2R locus, which encodes thymidine kinase), and beta-glucuronidase (at the A56R locus, which encodes hemagglutinin). This virus was tested in six human MPM cell lines (MSTO-211H, VAMT, JMN, H2373, H-2452, and H-2052). GLV-1h68 successfully infected all cell lines. For the most sensitive line, MSTO-211H, expression of green fluorescent protein (GFP) started within 4 hr with increasing intensity over time until nearly 100% of cells expressed GFP at 24 hr. All cell lines were sensitive to killing by GLV-1h68, with the degree of sensitivity predictable by infectivity assay. Even the most resistant cell line exhibited 44 +/- 3.8% cell survival by day 7 when infected at a multiplicity of infection of 1.0. Viral proliferation assays demonstrated 2-to 4-fold logarithmic replication of GLV-1h68 in the cell lines tested. In an orthotopic model, GLV-1h68 effectively prevented development of cachexia and tumor-related morbidity, reduced tumor burden, and cured MPM in both early and late treatment groups. GLV-1h68 was successfully used to treat MPM in vitro and in an orthotopic model (in vivo). These promising results warrant clinical investigation of GLV-1h68 as a novel agent in the treatment of MPM.