Replication of an adenoviral vector controlled by the human telomerase reverse transcriptase promoter causes tumor-selective tumor lysis.
Telomerase reactivation is a critical step for tumorigenesis, allowing cancer cells to proliferate indefinitely. Taking advantage of this property, we generated an adenovirus vector in which E1 gene expression, and therefore viral replication, is under control of the human telomerase reverse transcriptase (hTERT) promoter. This vector, referred to as Ad5-hTERT-E1, replicated in cancer cells and demonstrated efficient cancer-selective cytolysis in a variety of tumor cell lines, including HT-1080 (fibrosarcoma cells); HeLa (cervical carcinoma cells); A549 (lung carcinoma cells); Hep G2 (hepatocellular carcinoma cells); SCC-4, SCC-25, and SCCLSU-1 (head and neck squamous cell carcinoma cells); T24 (bladder carcinoma); and DU 145 (prostate carcinoma). In contrast, the identical multiplicities of infection of Ad5-hTERT-E1 had no effect on primary cultures of normal human fibroblasts, airway epithelial cells, and bone marrow mesenchymal stem cells. Moreover, a single injection of Ad5-hTERT-E1 into preexisting HT-1080 solid tumors, established s.c. in nu/nu mice, efficiently suppressed tumor growth. Interestingly, this conditionally replicating vector transactivated the replication of an E1-deleted antitumor adenoviral vector, Ad5-RSV-hsvTK, in tumor cells, demonstrating a synergistic antitumor effect in vivo. Combinational injection of a single dose of Ad5-hTERT-E1 and Ad5-RSV-hsvTK vector resulted in significant tumor suppression and regression after ganciclovir treatment. These results suggest that the Ad5-hTERT-E1 vector has potential as a broad-spectrum antitumor agent.
Lanson
Nicholas A
NA
Gene Therapy Program, Department of Medicine, Louisiana State University Health Sciences Center, 533 Bolivar Street, New Orleans, LA 70112, USA.
Friedlander
Paul L
PL
Schwarzenberger
Paul
P
Kolls
Jay K
JK
Wang
Guoshun
G
D017498:Adenovirus E1 Proteins / Q000235:genetics*; D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology*; D000328:Adult; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral; D004268:DNA-Binding Proteins; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000473:pathology / Q000628:therapy / Q000821:virology*; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication / Q000235:genetics / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D017498:Adenovirus E1 Proteins; D004268:DNA-Binding Proteins; D019098:Telomerase