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- Title
A tandemly repeated thyroglobulin core promoter has potential to enhance efficacy for tissue-specific gene therapy for thyroid carcinomas.
- Authors
Takeda, Teiji; Yamazaki, Masanori; Minemura, Kesami; Imai, Yosuke; Inaba, Hidehumi; Suzuki, Satoru; Miyamoto, Takahide; Ichikawa, Kazuo; Kakizawa, Tomoko; Mori, Jun-Ichirou; DeGroot, Leslie J.; Hashizume, Kiyoshi
- 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 (Ad2xTGtk) to obtain thyroid-specific cell killing ability. The transduction of HSVtk genes by infection with Ad2xTGtk 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 Ad2xTGtk 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), Ad2xTGtk and AdTGtk needed more than 100-fold concentrated GCV to reach IC[sub 50] compared to AdCMVtk. We confirmed the enhanced efficacy of Ad2xTGtk for tissue-specific cytotoxicity in vivo. After adenovirus/GCV treatment for FTC-133 tumorbearing nude mice, Ad2xTGtk enhanced tumor growth inhibition and survival rates compared to AdTGtk. Tumor growth inhibition and survival rates by Ad2 xTGtk were similar to that by AdCMVtk. Moreover, any toxic effect for rat normal tissues was not revealed after intravenous injections with Ad2xTGtk 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 Ad2xTGtk for tissue-specific gene therapy for TG-producing thyroid carcinomas without toxicity for normal tissues.
- Subjects
GENE therapy; THYROGLOBULIN; THYROID cancer
- Publication
Cancer Gene Therapy, 2002, Vol 9, Issue 10, p864
- ISSN
0929-1903
- Publication type
Article
- DOI
10.1038/sj.cgt.7700511