title: Conditionally replicative adenovirus driven by the human telomerase promoter provides broad-spectrum antitumor activity without liver toxicity.
abstract: 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.
authors.affiliation: Geron Corporation, Menlo Park, California 94025, USA.
authors.forename: John
authors.initials: J
authors.lastname: Irving
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.forename: Sandra
authors.initials: S
authors.lastname: Powell
authors.forename: Chris
authors.initials: C
authors.lastname: O'Sullivan
authors.forename: Michael
authors.initials: M
authors.lastname: Mok
authors.forename: Brian
authors.initials: B
authors.lastname: Murphy
authors.forename: Lisa
authors.initials: L
authors.lastname: Cardoza
authors.forename: Jane S
authors.initials: JS
authors.lastname: Lebkowski
authors.forename: Anish S
authors.initials: AS
authors.lastname: Majumdar
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D005260:Female; D005822:Genetic Vectors / Q000633:toxicity*; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000628:therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000628:therapy; D019098:Telomerase / Q000235:genetics*; D014779:Virus Replication; D014780:Viruses / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D017500:Adenovirus E1A Proteins; D004268:DNA-Binding Proteins; D019098:Telomerase