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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
Author(s) -
Miyauchi Motohiro,
Yoshida Yu,
Tada Yuji,
Narita Mitsuro,
Maeda Tomoko,
Bahar Rumana,
Kadomatsu Kenji,
Muramatsu Takashi,
Matsubara Shuichiro,
Nakagawara Akira,
Sakiyama Shigeru,
Tagawa Masatoshi
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/1097-0215(200002)9999:9999<::aid-ijc1112>3.0.co;2-x
Subject(s) - midkine , suicide gene , biology , thymidine kinase , microbiology and biotechnology , gene expression , promoter , gene , ganciclovir , reporter gene , herpes simplex virus , cancer research , therapeutic gene modulation , genetic enhancement , virology , virus , human cytomegalovirus , gene product , growth factor , genetics , receptor
A selective expression of suicide gene(s) in tumor cells should produce a preferential cytotoxic effect on tumors. Promoter region(s) of a gene that is expressed in tumors but not in normal tissues can be useful for tumor‐specific transcription of a suicide gene. Midkine (MK), a growth/differentiation factor, is expressed predominantly in various types of human tumors, whereas its expression in adult normal tissues is highly restricted. In our study, we showed that a 2.3‐kb fragment of genomic DNA in the 5′ upstream region 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 ‐acting sequence to permit expression of an exogenous gene in tumor cells was comparable with that of the SV40 promoter. Regulated expression of the herpes simplex virus‐thymidine kinase (HSV‐TK) gene under the control of the MK promoter 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 of the MK promoter could suppress the subsequent tumor growth. Expression of therapeutic genes restricted to tumors can be achieved by the use of the putative cis ‐acting MK promoter. © 2001 Wiley‐Liss, Inc.