In vivo imaging of adenovirus transduction and enhanced therapeutic efficacy of combination therapy with conditionally replicating adenovirus and adenovirus-p27.
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.
Lee
Choon-Taek
CT
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
Lee
Yoon-Jin
YJ
Kwon
Sung-Youn
SY
Lee
Jaeho
J
Kim
Kwang Il
KI
Park
Kyung-Ho
KH
Kang
Joo Hyun
JH
Yoo
Chul-Gyu
CG
Kim
Young Whan
YW
Han
Sung Koo
SK
Chung
June-Key
JK
Shim
Young-Soo
YS
Curiel
David T
DT
Carbone
David P
DP
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
D050760:Cyclin-Dependent Kinase Inhibitor p27; D008156:Luciferases