Combined antitumor gene therapy with herpes simplex virus-thymidine kinase and short hairpin RNA specific for mammalian target of rapamycin

Woo,Ha-Na; Lee,Won  Il; Kim,Ji  Hyun; Ahn,Jeonghyun; Han,Jeong  Hee; Lim,Sue  Yeon; Lee,Won  Woo; Lee,Heuiran

doi:10.3892/ijo.2015.3194

Combined antitumor gene therapy with herpes simplex virus-thymidine kinase and short hairpin RNA specific for mammalian target of rapamycin

Authors:
- Ha-Na Woo
- Won Il Lee
- Ji Hyun Kim
- Jeonghyun Ahn
- Jeong Hee Han
- Sue Yeon Lim
- Won Woo Lee
- Heuiran Lee
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Affiliations: Department of Microbiology, University of Ulsan College of Medicine, Seoul, Republic of Korea, Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
Published online on: October 8, 2015 https://doi.org/10.3892/ijo.2015.3194
Pages: 2233-2239

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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.

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