A telomerase-dependent conditionally replicating adenovirus for selective treatment of cancer.
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.
Wirth
Thomas
T
Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, 30625 Hannover, Germany.
Zender
Lars
L
Schulte
Bernd
B
Mundt
Bettina
B
Plentz
Ruben
R
Rudolph
Karl Lenhard
KL
Manns
Michael
M
Kubicka
Stefan
S
Kühnel
Florian
F
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
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