Conditionally replicating adenovirus improves gene replication efficiency and anticancer effect of E1-deleted adenovirus carrying TRAIL in head and neck squamous cell carcinoma.
To overcome the low efficiency of gene therapy, we combined a conditionally replicating adenovirus (CRAd) and an adenoviral vector with a therapeutic gene. CRAd has an oncolytic activity in cancer cells with abnormal Rb activity and helps the replication of therapeutic genes incorporated in the E1-deleted adenovirus. We investigated the anticancer effect of a combination of CRAd and adenovirus carrying tumor necrosis factor-related apoptosis inducing ligand (ad-TRAIL). We expected to see increased gene expression in cancer cells as well as an antitumor effect. With the combined application of CRAd and ad-luciferase in head and neck cancer cell lines, we observed considerably increased luciferase activity that was 10- to 50-fold greater than with ad-luciferase alone. The combination of CRAd and ad-TRAIL showed significant suppression of growth in cell lines and increased the sub-G(1) portion of cells 30-fold compared to any single treatment. The expression of TRAIL was highly amplified by the combined treatment and was accompanied by expression of molecules related to apoptosis. In a xenograft animal model, mice treated with CRAd and ad-TRAIL showed complete regression of established tumors, whereas mice treated with CRAd or ad-TRAIL alone did not. In conclusion, this combined strategy using CRAd and adenovirus carrying a therapeutic gene increased the gene transfer rate and enhanced antitumor effects. We expect that this combination strategy could be extended to a multitarget cancer gene therapy by combining multiple adenoviruses and CRAd.
Shim
Seon-Hui
SH
Department of Molecular Tumor Biology, College of Medicine, Seoul National University, Seoul, Korea.
Lee
Choon-Taek
CT
Hun Hah
J
J
Lee
Jae-Jung
JJ
Park
Seok-Woo
SW
Heo
Dae Seog
DS
Sung
Myung-Whun
MW
D000256:Adenoviridae / Q000502:physiology*; D017498:Adenovirus E1 Proteins / Q000502:physiology*; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D015316:Genetic Therapy; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D050130:Oncolytic Virotherapy; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D017498:Adenovirus E1 Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand