title: In vivo imaging of adenovirus transduction and enhanced therapeutic efficacy of combination therapy with conditionally replicating adenovirus and adenovirus-p27.
abstract: Gene therapy is hampered by poor gene transfer to the tumor mass. We previously proposed a combination adenoviral gene therapy containing a conditionally replicating adenovirus (CRAD) expressing mutant E1 (delta24RGD) and a replication-defective E1-deleted adenovirus to enhance the efficiency of gene transfer. Mutant E1 expressed by delta24RGD enables the replication of replication-defective adenoviruses in tumors when cancer cells are co-infected with both viruses. In this study, gene transfer rates in xenografts tumors were monitored by bioluminescence in cells infected with the replication-defective adenovirus-luciferase (ad-luc). Tumor masses treated with CRAD + ad-luc showed dramatically stronger and more prolonged luciferase expression than ad-luc-treated tumors and this expression spread through the entire tumor mass without significant systemic spread. Transduction with CRAD + replication-defective adenovirus-p27 increased the expression of p27 by 24-fold versus transduction with ad-p27 alone. Treatment of a lung cancer cell line and of established lung cancer xenografts with CRAD + adenovirus-p27 also induced stronger growth suppression than treatment with either virus alone. These findings confirm the selective replication of E1-deleted adenovirus containing a therapeutic gene due to the presence of mutant E1 produced by delta24RGD in tumors. Moreover, this replication increased the therapeutic gene transfer rate and enhanced its antitumor effects.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Lung Institute of Medical Research Center, Seoul National University College of Medicine, Seoul, Korea. ctlee@snu.ac.kr
authors.forename: Choon-Taek
authors.initials: CT
authors.lastname: Lee
authors.forename: Yoon-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Sung-Youn
authors.initials: SY
authors.lastname: Kwon
authors.forename: Jaeho
authors.initials: J
authors.lastname: Lee
authors.forename: Kwang Il
authors.initials: KI
authors.lastname: Kim
authors.forename: Kyung-Ho
authors.initials: KH
authors.lastname: Park
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Kang
authors.forename: Chul-Gyu
authors.initials: CG
authors.lastname: Yoo
authors.forename: Young Whan
authors.initials: YW
authors.lastname: Kim
authors.forename: Sung Koo
authors.initials: SK
authors.lastname: Han
authors.forename: June-Key
authors.initials: JK
authors.lastname: Chung
authors.forename: Young-Soo
authors.initials: YS
authors.lastname: Shim
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D000818:Animals; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008163:Luminescent Measurements; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D051379:Mice; D014161:Transduction, Genetic; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D050760:Cyclin-Dependent Kinase Inhibitor p27; D008156:Luciferases