Conditionally replicative adenovirus driven by the human telomerase promoter provides broad-spectrum antitumor activity without liver toxicity
Conditionally replicative adenovirus driven by the human telomerase promoter provides broad-spectrum antitumor activity without liver toxicity
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DOI：
10.1038/sj.cgt.7700666
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发表时间：
2004-03-01
影响因子：
6.4
通讯作者：
Majumdar, AS
中科院分区：
文献类型：
--
作者：
Irving, J;Wang, Z;Majumdar, AS
已知人端粒酶逆转录酶（hTERT）启动子在许多表达hTERT（端粒酶核糖核蛋白复合物的催化组分）的人癌细胞中选择性地驱动转基因表达。我们已经创建了一种条件复制型腺病毒，其中病毒复制所需的病毒E1 A基因处于hTERT启动子（AdhTERTp-E1 A）的控制下。AdhTERTp-E1A病毒对多种正常和肿瘤细胞系的体外研究表明，病毒基因组复制和生产性感染主要限于端粒酶阳性肿瘤细胞。在测试的正常原代成纤维细胞和上皮细胞系中未观察到裂解复制。在体内的病毒给药到荷人肝或前列腺肿瘤异种移植物的裸鼠产生显着的肿瘤减少，并在某些情况下，导致完全的肿瘤消退。AdhTERTp-E1A病毒在正常小鼠肝脏中不主动表达E1A，与其中CMV启动子（AdCMVp-E1A）驱动E1A基因的对照溶瘤载体相反。此外，AdhTERTp-E1A病毒对全身注射小鼠的肝脏没有明显的毒性。hTERT启动子驱动的溶瘤病毒对新鲜培养的人肝细胞的毒性也显著降低。这些研究表明，由端粒酶启动子驱动的溶瘤病毒可用于有效杀死多种癌细胞类型，并具有治疗不同来源的原发性和转移性癌症的潜力。
The human telomerase reverse transcriptase (hTERT) promoter is known to selectively drive transgene expression in many human cancer cells expressing hTERT, the catalytic component of the telomerase ribonucleoprotein complex. We have created a conditionally replicative adenovirus where the viral E1A gene, which is required for viral replication, is under the control of the hTERT promoter (AdhTERTp-E1A). In vitro studies with AdhTERTp-E1A virus on a variety of normal and tumor cell lines have shown that viral genome replication and productive infection is primarily restricted to telomerase-positive tumor cells. Lytic replication was not observed in normal primary fibroblast and epithelial cell lines tested. In vivo administration of the virus into nude mice bearing human liver or prostate tumor xenografts produced significant tumor reduction and, in some cases, resulted in complete tumor regression. AdhTERTp-E1A virus did not actively express E1A in normal mouse liver, in contrast to a control oncolytic vector in which the CMV promoter (AdCMVp-E1A) was driving the E1A gene. In addition, AdhTERTp-E1A virus produced no apparent toxicity to the liver in systemically injected mice. The hTERT promoter-driven oncolytic virus also produced significantly less toxicity to freshly cultured human hepatocytes. These studies demonstrate that an oncolytic virus driven by the telomerase promoter can be used to effectively kill a wide variety of cancer cell types and has the potential to treat primary and metastatic cancer of diverse origins.