IN-VIVO ADENOVIRUS-MEDIATED PRODRUG GENE-THERAPY FOR CARCINOEMBRYONICANTIGEN-PRODUCING PANCREATIC-CANCER

In gene therapy for malignancy, the herpes simplex virus thymidine kin ase (HSVtk)-ganciclovir (GCV) system has been widely used. For pancrea tic cancer targeting, we estimated the therapeutic efficacy of gene tr ansduction by an adenovirus-carrying HSVtk gene under the control of a carcinoembryonic antigen (CEA) promoter (AdCEAtk) followed by systemi c administration of GCV, Four cell lines, CEA-producing Su.86.86, BxPC -3 (pancreatic cancer cells), MKN45 (gastric cancer cells) and CEA-non producing HeLa, were used for analysis of GCV sensitivity induced by a denoviral gene transduction, To evaluate the therapeutic efficacy of A dCEAtk and GCV administration in human CEA-positive pancreatic cancer ill vivo, a subcutaneously implanted tumor-bearing nude mouse model wa s used. When the HSVtk gene was transduced with a ubiquitous promoter into these cells, increase of the GCV sensitivity was independent of C EA-production, In contrast, when the cells were transduced with a CEA promoter, the cell-killing effect of GCV was increased in only CEA-pro ducing cells, For in vivo analysis, AdCEAtk was delivered into subcuta neously established tumors of Su.86.86 cells. Immunohistochemical stai ning of the tumor showed that HSVtk protein was expressed only in tumo r cells, and tumor growth was markedly suppressed by administration of GCV, These results suggest that the adenovirus-mediated transfer of H SVtk gene with CEA promoter specifically increases the GCV sensitivity of CEA-producing pancreatic cancer cells in vitro and in vivo. This s trategy may provide a useful tool for treating pancreatic cancer, espe cially CEA-producing tumor cells.