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In Vivo Selective Gene Expression and Therapy Mediated by Adenoviral Vectors for Human Carcinoembryonic Antigen-producing Gastric Carcinoma¹

Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113 [K-H. L., F. K., Y. S., M. Oh., T. T., T. O., M. Om.], and Department of Molecular Biotherapy Research, Cancer Chemotherapy Center, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 170 [F. K., Y. Y., H. H.], Japan

Previously, we reported that adenoviral vectors carrying the carcinoembryonic antigen (CEA) promoter sequences to direct the Echerichia coli ß-galactosidase gene (AdCEA-lacZ) or cytosine deaminase (CD) gene (Ad-CEA-CD) confer selective gene expression on a CEA-positive gastric cancer cell line (MKN45) in vitro. Here, adenovirus-mediated tumor-specific gene therapy for CEA-positive gastric carcinoma in vivo was investigated. Using an animal model with i.p. disseminated MKN45 tumors, adenovirus-mediated tumor-specific transgene expression and therapeutic efficacy were analyzed. After an i.p. injection of AdCEA-lacZ, ß-galactosidase activity was confined to tumor xenografts. Moreover, CD mRNA was expressed exclusively in MKN45 tumor xenografts after infection with AdCEA-CD, despite the fact that an adenovirus-mediated transfer of CD DNA was detected in all tissues tested. In contrast, CD mRNA was detected not only in tumor xenografts but also in other organs of mice infected with AdCA-CD, in which CD gene expression is governed by an ubiquitous promoter. Suppression of tumor growth and prolongation of survival were noted in tumor-bearing mice treated with AdCEA-CD and 5-fluorocytosine (5FC) without observable adverse effects. In contrast, significant hepatic toxicity was noted in animals treated with AdCA-CD. These results reveal that the CEA promoter restricts CD gene expression to CEA-positive tumor cells in the adenoviral context in vivo, along with the beneficial therapeutic effects of 5FC treatment, suggesting the i.p. AdCEA-CD/5FC system may provide a novel approach to treatment of i.p. disseminated gastric cancer.

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

² To whom requests for reprints should be addressed, at Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. Phone: 81-3-3815-5411 ext. 3070; Fax: 81-3-3814-0021.

Received 3/10/97. Accepted 7/29/97.

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