TY - JOUR
T1 - Gene expression in intrahepatic tumors through DNA recombination by a replication-activated adenovirus vector
AU - Huang, Xiao W.
AU - Lieber, Andre
AU - Tang, Zhao Y.
AU - Lawrence, Theodore S.
AU - Moyer, Mary P.
AU - Zhang, Ming
N1 - Funding Information:
Address correspondence and reprint requests to: Ming Zhang, Department of Radiation Oncology, University of Michigan, 1331 E Ann Street, Room 3111, Ann Arbor, MI 48109-0582, USA. E-mail: [email protected] Supported by NIH grants CA80145, CA84117, Cancer Center Core Grant CA46592.
PY - 2004/6
Y1 - 2004/6
N2 - One strategy for improving selectivity of gene therapy is the use of a replication-activated adenovirus vector that mediates transgene expression specifically in tumor cells through homologous recombination of viral genomes. In this study, we compared replication-activated adenovirus containing inverted repeats (Ad.IR-BG) with IR-deficient virus (Ad.BG) for selective gene expression in hepatocellular carcinoma and colon carcinoma metastases in the liver. We found that Ad.IR-BG conferred specific gene expression in both carcinoma cells, with minimal expression in hepatocytes and colon epithelial cells. This occurred through viral DNA recombination in Ad.IR-BG-infected tumor cells but not in normal cells. Hydroxyurea, which blocks DNA replication, inhibited DNA recombination and β-gal expression in Ad.IR-BG-infected but not Ad.BG-infected tumor cells. Finally, systemic injection of Ad.IR-BG into tumor xenografts in nude mice significantly improved selectivity of gene expression in tumors with minimal expression in normal tissues. Viral DNA recombination, which was absent in normal liver, was detected in Ad.IR-BG-infected tumors but not in Ad.BG-infected tissue. These findings demonstrated that replication-activated adenovirus can mediate tumor-specific gene expression through viral DNA recombination, which is otherwise deficient in normal cells.
AB - One strategy for improving selectivity of gene therapy is the use of a replication-activated adenovirus vector that mediates transgene expression specifically in tumor cells through homologous recombination of viral genomes. In this study, we compared replication-activated adenovirus containing inverted repeats (Ad.IR-BG) with IR-deficient virus (Ad.BG) for selective gene expression in hepatocellular carcinoma and colon carcinoma metastases in the liver. We found that Ad.IR-BG conferred specific gene expression in both carcinoma cells, with minimal expression in hepatocytes and colon epithelial cells. This occurred through viral DNA recombination in Ad.IR-BG-infected tumor cells but not in normal cells. Hydroxyurea, which blocks DNA replication, inhibited DNA recombination and β-gal expression in Ad.IR-BG-infected but not Ad.BG-infected tumor cells. Finally, systemic injection of Ad.IR-BG into tumor xenografts in nude mice significantly improved selectivity of gene expression in tumors with minimal expression in normal tissues. Viral DNA recombination, which was absent in normal liver, was detected in Ad.IR-BG-infected tumors but not in Ad.BG-infected tissue. These findings demonstrated that replication-activated adenovirus can mediate tumor-specific gene expression through viral DNA recombination, which is otherwise deficient in normal cells.
KW - Colorectal neoplasms
KW - Liver neoplasms
KW - Recombination
KW - Replication-activated adenovirus
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U2 - 10.1038/sj.cgt.7700719
DO - 10.1038/sj.cgt.7700719
M3 - Article
C2 - 15073612
AN - SCOPUS:2942557213
SN - 0929-1903
VL - 11
SP - 450
EP - 456
JO - Cancer Gene Therapy
JF - Cancer Gene Therapy
IS - 6
ER -