title: Combined antitumor gene therapy with herpes simplex virus-thymidine kinase and short hairpin RNA specific for mammalian target of rapamycin.
abstract: A proof-of-concept study is presented using dual gene therapy that employed a small hairpin RNA (shRNA) specific for mammalian target of rapamycin (mTOR) and a herpes simplex virus-thymidine kinase (HSV-TK) gene to inhibit the growth of tumors. Recombinant adeno-associated virus (rAAV) vectors containing a mutant TK gene (sc39TK) were transduced into HeLa cells, and the prodrug ganciclovir (GCV) was administered to establish a suicide gene-therapy strategy. Additionally, rAAV vectors expressing an mTOR-targeted shRNA were employed to suppress mTOR-dependent tumor growth. GCV selectively induced death in tumor cells expressing TK, and the mTOR-targeted shRNA altered the cell cycle to impair tumor growth. Combining the TK-GCV system with mTOR inhibition suppressed tumor growth to a greater extent than that achieved with either treatment alone. Furthermore, HSV-TK expression and mTOR inhibition did not mutually interfere with each other. In conclusion, gene therapy that combines the TK-GCV system and mTOR inhibition shows promise as a novel strategy for cancer therapy.
authors.affiliation: Department of Microbiology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Ha-Na
authors.initials: HN
authors.lastname: Woo
authors.affiliation: Department of Microbiology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Won Il
authors.initials: WI
authors.lastname: Lee
authors.affiliation: Department of Microbiology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Microbiology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jeonghyun
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jeong Hee
authors.initials: JH
authors.lastname: Han
authors.affiliation: Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sue Yeon
authors.initials: SY
authors.lastname: Lim
authors.affiliation: Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Won Woo
authors.initials: WW
authors.lastname: Lee
authors.affiliation: Department of Microbiology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Heuiran
authors.initials: H
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D015153:Blotting, Western; D000229:Dependovirus; D015774:Ganciclovir / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000628:therapy*; D034741:RNA, Small Interfering; D018139:Simplexvirus / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics*; D014161:Transduction, Genetic; D014764:Viral Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D034741:RNA, Small Interfering; D014764:Viral Proteins; C546842:MTOR protein, human; D013937:Thymidine Kinase; D058570:TOR Serine-Threonine Kinases; D015774:Ganciclovir