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In Vivo Gene Therapy for -Fetoprotein-producing Hepatocellular Carcinoma by Adenovirus-mediated Transfer of Cytosine Deaminase Gene¹

Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan [F. K., K-H. L., Y. S., T. Tan., M. Oh., T. O., M. Om.]; Department of Molecular Biotherapy Research, Cancer Chemotherapy Center, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-lkebukuro, Toshima-ku, Tokyo 170, Japan [F. K., Y. Y., H. W., H. H.]; and Department of Medical Biochemistry, University of Calgary, Calgary, Alberta T2N 4N1, Canada [H. N., T. Tam.]

The -fetoprotein (AFP) gene is normally expressed in fetal liver and is transcriptionally silent in adult liver but overexpressed in human hepatocellular carcinoma (HCC). Here, we demonstrate that replication defective recombinant adenoviral vectors, containing the human AFP promoter/enhancer, can be used to express the Escherichia coli cytosine deaminase (CD) gene (AdAFPCD) and the ß-galactosidase gene (AdAF-PlacZ) in AFP-producing HCC cell lines. Expression of the CD gene by adenovirus from the AFP promoter/enhancer (AdAFPCD) induced cells sensitive to 5-fluorocytosine (5FC) in the AFP-producing cells but not in the AFP-nonproducing cells. Transduction by an adenoviral vector harboring an ubiquitous strong promoter and CD gene showed enzymatic activity and 5FC killing in all cell lines. When AdAFPlacZ was injected into the s.c. established hepatoma in vivo, expression of the ß-galactosidase gene was confined to AFP-producing HCC xenografts. Moreover, HCC xenografts regressed by transduction with AdAFPCD and subsequently with 5FC treatment in vivo. These findings suggest that utilization of the AFP promoter/enhancer in an adenoviral vector can confer selective expression of a heterologous suicide gene in hepatocellular carcinoma cells in vitro and in vivo.

¹ This work was supported by research grants from the Ministry of Education, Science and Culture of Japan, Kanae Foundation of Research for New Medicine, Sagawa Foundation for Promotion of Cancer Research, and Foundation for Advancement of International Science (to F. K.). F. K. is a Research Fellow of the Japan Society for the Promotion of Science.

² To whom requests for reprints should be addressed. Phone: 3-3815-5411, ext. 3070; Fax: 3-3814-0021.

Received 6/ 3/96. Accepted 12/ 4/96.

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