Expression of herpes simplex virus-thymidine kinase gene controlled by a promoter region of the midkine gene confers selective cytotoxicity to ganciclovir in human carcinoma cells

A selective expression of suicide gene(s) in tumor cells should produce a p referential cytotoxic effect on tumors. Promoter region(s) of a gene that i s expressed in tumors but not in normal tissues can be useful for tumor-spe cific transcription of a suicide gene. Midkine (MK), a growth/differentiati on factor, is expressed predominantly in various types of human tumors, whe reas its expression in adult normal tissues is highly restricted. In our st udy, we showed that a 2.3-kb fragment of genomic DNA in the 5' upstream reg ion of the MK gene could activate transcription of a fused reporter gene in MK-positive cells but not in MK-negative cells. Efficiency of the cis-acti ng sequence to permit expression of an exogenous gene in tumor cells was co mparable with that of the SV40 promoter. Regulated expression of the herpes simplex virus-thymidine kinase (HSV-TK) gene under the control of the MK p romoter conferred increased sensitivity to ganciclovir (GCV) on MK-positive tumor cells. Administration of GCV into nude mice that were implanted with MK-positive tumor cells that expressed the HSV-TK gene under the control o f the MK promoter could suppress the subsequent tumor growth. Expression of therapeutic genes restricted to tumors can be achieved by the use of the p utative cis-acting MK promoter. (C) 2001 Wiley-Liss, Inc.