Suicide gene therapy for gastrointestinal tumors using tumor-specific promoters

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Tumor-specific gene expression is important for improved safely and enhanced efficacy of gene therapy for cancer. We then examined promoter regions of the midkine gene which was expressed in tumors but not in normal surrounding tissues or that of the c-erbB-2 and vascular endothelial growth factor gene whose expressions were predominantly found in the tumors of upper gastrointesinal tract and a number of solid tumors, respectively. Our results were as follows. (1)The midkine gene was expressed in 8 out of 14 human esophageal specimens and 14 out of 15 hepatocellular carcinoma specimnens, whereas none of non-tumorous regions of the same patients were negative for the expression. (2)Reporter assays using deletion mutants of the promoter region of the midkine gene showed that the 550-bp fragment was responsible for tumor-specific transcriptional activation. (3)The 250-bp fragment of 5'-upstream region of the c-erbB-2 gene strongly drove the transcription of the fused reporter gene in tumors but not in normal fibroblasts. (4)The 1.2-kb promoter region of the vascular endothelial growth factor gene had a cis-acting element for hypoxic responsiveness. (5)Forced expression of the herpes simplex virus-thymine kinase gene using these linked promoters conferred increased sensitivity of the transfected vells to ganciclovir. (6)The deoxycytidine kinase/ara-C and the uracil phosphoribosyl transferase/5-FU systems were useful for cell killing together with an appropriate promoter.