title: A telomerase-dependent conditionally replicating adenovirus for selective treatment of cancer.
abstract: The catalytic component of human telomerase reverse transcriptase (hTERT) is not expressed in most primary somatic human cells, whereas the majority of cancer cells reactivate telomerase by transcriptional up-regulation of hTERT. Several studies demonstrated that the hTERT promoter can be used to restrict gene expression of E1-deleted replication defective adenoviral vectors to telomerase-positive cancer cells. In this study, a conditionally replicating adenovirus (hTERT-Ad) expressing E1A genes under control of a 255-bp hTERT-promoter was constructed. Additionally, an internal ribosomal entry site-enhanced green fluorescent protein cassette was inserted downstream of the E1B locus to monitor viral replication in vivo. Adenoviral replication of hTERT-Ad and enhancement of enhanced green fluorescent protein expression could be observed in all investigated telomerase-positive tumor cell lines. In contrast, hTERT-Ad infection of telomerase-negative primary human hepatocytes did not result in significant replication. The capability of hTERT-Ad to induce cytopathic effects in tumor cells was comparable with that of adenovirus wild type and significantly higher compared with ONYX-015, regardless of the p53 status of the tumor cells. Single application of low-dose hTERT-Ad to tumor xenografts led to significant inhibition of tumor growth, confirming the potential therapeutic value of conditionally replicative adenoviral vectors. These in vivo experiments also revealed that hTERT-Ad-mediated oncolysis was more efficient than ONYX-015 treatment. These results demonstrate that expression of E1A under transcriptional control of the hTERT promoter is sufficient for effective telomerase-dependent adenovirus replication as a promising perspective for the treatment of the majority of epithelial tumors.
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, 30625 Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: Bernd
authors.initials: B
authors.lastname: Schulte
authors.forename: Bettina
authors.initials: B
authors.lastname: Mundt
authors.forename: Ruben
authors.initials: R
authors.lastname: Plentz
authors.forename: Karl Lenhard
authors.initials: KL
authors.lastname: Rudolph
authors.forename: Michael
authors.initials: M
authors.lastname: Manns
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicka
authors.forename: Florian
authors.initials: F
authors.lastname: Kühnel
mesh_terms: D000256:Adenoviridae; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000260:Adenoviruses, Human / Q000502:physiology*; D000818:Animals; D001691:Biological Therapy; D006528:Carcinoma, Hepatocellular / Q000556:secondary*; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006367:HeLa Cells / Q000821:virology; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D016233:Immunotherapy, Active; D008113:Liver Neoplasms / Q000473:pathology*; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000502:physiology; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013047:Specific Pathogen-Free Organisms; D016385:TATA Box; D019098:Telomerase / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000821:virology; D014765:Viral Vaccines / Q000627:therapeutic use; D014779:Virus Replication / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D017500:Adenovirus E1A Proteins; D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D014765:Viral Vaccines; C464532:dl1520; D049452:Green Fluorescent Proteins; D019098:Telomerase