ADENOVIRUS-MEDIATED PRODRUG GENE-THERAPY FOR CARCINOEMBRYONIC ANTIGEN-PRODUCING HUMAN GASTRIC-CARCINOMA CELLS IN-VITRO

We analyzed the ability of a recombinant replication-defective adenovi rus vector with the carcinoembryonic antigen (CEA) promoter to transfe r the thymidine kinase gene of herpes simplex virus (HSVtk) into gastr ic cancer cells to confer sensitivity to ganciclovir (GCV). CEA-produc ing gastric cancer cell lines (MKN28 and MKN45), a CEA-nonproducing ga stric cancer cell line (MKN1), and a human uterine cervical cancer cel l line (HeLa) were infected with a recombinant adenovirus carrying lac Z reporter gene coupled to the CEA promoter (AdCEAlacZ). The efficienc y of AdCEAlacZ-mediated gene transfer was correlated with the amount o f CEA produced by each cell line. Furthermore, the 50% growth inhibito ry concentrations (IC50) of GCV were 21 and 5.8 mu M for MKN28 and MKN 45, respectively, when infected with a recombinant adenovirus carrying the HSVtk gene coupled to the CEA promoter (AdCEAtk). However, MKN1 a nd HeLa cells infected with AdCEAtk remained resistant to GCV (IC50 > 300 mu M of GCV). In addition, a bystander killing effect was demonstr ated against MKN45 cells when only 20% of AdCEAtk-infected cells were mixed with uninfected cells. These data indicate the potential for tar geted gene therapy using the cell type-specific promoter of the CEA ge ne against gastric cancers that produce CEA.