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In vivo Imaging of Adenovirus Transduction and Enhanced Therapeutic Efficacy of Combination Therapy with Conditionally Replicating Adenovirus and Adenovirus-p27

¹ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Lung Institute of Medical Research Center, and ² Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea; ³ Department of Medicine and Respiratory Center, Seoul National University Bundang Hospital, Seongnam, Korea; ⁴ Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; and ⁵ Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Choon-Taek Lee, Department of Medicine, Seoul National University Bundang Hospital, 300 Gumi-Dong, Seongnam 463-707, Korea. Phone: 82-31-787-7002; Fax: 82-31-787-4052; E-mail: ctlee{at}snu.ac.kr.

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 (24RGD) and a replication-defective E1-deleted adenovirus to enhance the efficiency of gene transfer. Mutant E1 expressed by 24RGD 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 24RGD in tumors. Moreover, this replication increased the therapeutic gene transfer rate and enhanced its antitumor effects. (Cancer Res 2006; 66(1): 372-7)