Irving John, Wang Zhuo, Powell Sandra, O'Sullivan Chris, Mok Michael, Murphy Brian, Cardoza Lisa, Lebkowski Jane S, Majumdar Anish S
Geron Corporation, Menlo Park, California 94025, USA.
Cancer Gene Ther. 2004 Mar;11(3):174-85. doi: 10.1038/sj.cgt.7700666.
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.
人端粒酶逆转录酶（hTERT）启动子已知可在许多表达hTERT（端粒酶核糖核蛋白复合物的催化成分）的人类癌细胞中选择性驱动转基因表达。我们构建了一种条件复制腺病毒，其中病毒复制所需的病毒E1A基因受hTERT启动子控制（AdhTERTp-E1A）。对AdhTERTp-E1A病毒在多种正常和肿瘤细胞系上进行的体外研究表明，病毒基因组复制和有效感染主要局限于端粒酶阳性肿瘤细胞。在所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。将该病毒体内注射到携带人肝或前列腺肿瘤异种移植的裸鼠体内可显著减小肿瘤大小，在某些情况下，还可导致肿瘤完全消退。与由巨细胞病毒启动子（AdCMVp-E1A）驱动E1A基因的对照溶瘤载体相反，AdhTERTp-E1A病毒在正常小鼠肝脏中不活跃表达E1A。此外，AdhTERTp-E1A病毒对全身注射的小鼠肝脏没有明显毒性。hTERT启动子驱动的溶瘤病毒对新鲜培养的人肝细胞产生的毒性也显著较小。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，并具有治疗多种起源的原发性和转移性癌症的潜力。
