IN-VIVO SELECTIVE GENE-EXPRESSION AND THERAPY MEDIATED BY ADENOVIRAL VECTORS FOR HUMAN CARCINOEMBRYONIC ANTIGEN-PRODUCING GASTRIC-CARCINOMA

Previously, we reported that adenoviral vectors carrying the carcinoem bryonic antigen (CEA) promoter sequences to direct the Echerichia coli beta-galactosidase gene (AdCEA-lacZ) or cytosine deaminase (CD) gene (AdCEA-CD) confer selective gene expression on a CEA-positive gastric cancer cell line (MKN45) in vitro, Here, adenovirus-mediated tumor-spe cific gene therapy for CEA-positive gastric carcinoma in vivo was inve stigated, Using an animal model with i.p. disseminated MKN45 tumors, a denovirus-mediated tumor-specific transgene expression and therapeutic efficacy were analyzed, After an i.p. injection of AdCEA-lacZ, beta-g alactosidase activity was confined to tumor xenografts, Moreover, CD m RNA was expressed exclusively in MKN45 tumor xenografts after infectio n with AdCEA-CD, despite the fact that an adenovirus-mediated transfer of CD DNA was detected in all tissues tested, In contrast, CD mRNA wa s detected not only in tumor xenografts but also in other organs of mi ce infected with AdCA-CD, in which CD gene expression is governed by a n 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-C D. These results reveal that the CEA promoter restricts CD gene expres sion to CEA-positive tumor cells in the adenoviral context in vivo, al ong with the beneficial therapeutic effects of 5FC treatment, suggesti ng the i.p. AdCEA-CD/5FC system may provide a novel approach to treatm ent of i.p. disseminated gastric cancer.