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  • Original Article
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A tandemly repeated thyroglobulin core promoter has potential to enhance efficacy for tissue-specific gene therapy for thyroid carcinomas

Cancer Gene Therapy volume 9, pages 864–874 (2002)Cite this article

Abstract

Recombinant adenoviruses, carrying herpes simplex virus thymidine kinase (HSVtk) genes, were developed to evaluate the possibility of tissue-specific gene therapy for thyroid carcinomas. The HSVtk gene was driven by a minimal thyroglobulin (TG) promoter (AdTGtk) and a tandemly repeated minimal TG promoter (Ad2×TGtk) to obtain thyroid-specific cell killing ability. The transduction of HSVtk genes by infection with Ad2×TGtk followed by ganciclovir (GCV) treatment showed more powerful cytotoxicity for TG-producing FRTL5 cells, a rat normal thyroid cell line, and FTC-133 cells, a human follicular thyroid carcinoma cell line, than when infected with AdTGtk in vitro. The cell killing ability of Ad2×TGtk was 10- to 30-fold higher than that of AdTGtk and similar to that of AdCMVtk, which carries HSVtk under the control of CMV promoter. Whereas after treatment with adenovirus/GCV to non–TG-producing cell lines (undifferentiated thyroid carcinoma cell lines and carcinoma cell lines from other tissues), Ad2×TGtk and AdTGtk needed more than 100-fold concentrated GCV to reach IC50 compared to AdCMVtk. We confirmed the enhanced efficacy of Ad2×TGtk for tissue-specific cytotoxicity in vivo. After adenovirus/GCV treatment for FTC-133 tumor-bearing nude mice, Ad2×TGtk enhanced tumor growth inhibition and survival rates compared to AdTGtk. Tumor growth inhibition and survival rates by Ad2×TGtk were similar to that by AdCMVtk. Moreover, any toxic effect for rat normal tissues was not revealed after intravenous injections with Ad2×TGtk and intraperitoneal administrations with GCV in vivo, whereas severe liver damages were observed after treatment with AdCMVtk/GCV. These data indicate a beneficial effect of Ad2×TGtk for tissue-specific gene therapy for TG-producing thyroid carcinomas without toxicity for normal tissues.

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Acknowledgements

We are grateful to RD Lauro for providing the pTGCAT vector, SLC Woo for the pBS-tk plasmid, and S Refetoff for the pJM17 plasmid and AdTKluc. We also thank F Hoffmann-La Roche for providing GCV.

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Authors and Affiliations

  1. Department of Aging Medicine and Geriatrics, Shinshu University, School of Medicine, Matsumoto, Nagano, Japan

    Teiji Takeda, Kesami Minemura, Hidehumi Inaba, Satoru Suzuki, Takahide Miyamoto, Kazuo Ichikawa, Tomoko Kakizawa, Jun-Ichirou Mori & Kiyoshi Hashizume

  2. Department of Medicine, Thyroid Study Unit, The University of Chicago, Chicago, 60637, Illinois, USA

    Masanori Yamazaki & Leslie J DeGroot

  3. Discovery Research Planning, R&D, Kissei Pharmaceutical Co., LTD, Matsumoto, Nagano, Japan

    Yosuke Imai

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  1. Teiji Takeda
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  2. Masanori Yamazaki
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Correspondence to Teiji Takeda.

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Takeda, T., Yamazaki, M., Minemura, K. et al. A tandemly repeated thyroglobulin core promoter has potential to enhance efficacy for tissue-specific gene therapy for thyroid carcinomas. Cancer Gene Ther 9, 864–874 (2002). https://doi.org/10.1038/sj.cgt.7700511

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