| 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 x TGtk) to obtain thyroid-specific cell killing ability. The transduction of HSVtk genes by infection with Ad2 x 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 x 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 x TGtk and AdTGtk needed more than 100-fold concentrated GCV to reach IC(50) compared to AdCMVtk. We confirmed the enhanced efficacy of Ad2 x TGtk for tissue-specific cytotoxicity in vivo. After adenovirus/GCV treatment for FTC-133 tumor-bearing nude mice, Ad2 x TGtk enhanced tumor growth inhibition and survival rates compared to AdTGtk. Tumor growth inhibition and survival rates by Ad2 x TGtk were similar to that by AdCMVtk. Moreover, any toxic effect for rat normal tissues was not revealed after intravenous injections with Ad2 x 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 x TGtk for tissue-specific gene therapy for TG-producing thyroid carcinomas without toxicity for normal tissues. |
| Authors | Teiji Takeda, Masanori Yamazaki, Kesami Minemura, Yosuke Imai, Hidehumi Inaba, Satoru Suzuki, Takahide Miyamoto, Kazuo Ichikawa, Tomoko Kakizawa, Jun-Ichirou Mori, Leslie J DeGroot, Kiyoshi Hashizume
(Affiliation: Department of Aging Medicine and Geriatrics, Shinshu University, School of Medicine, Matsumoto, Nagano, Japan. teiji at hsp.md.shinshu-u.ac.jp)
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| Journal | Cancer gene therapy
(Cancer Gene Ther)
Vol. 9
Issue 10
Pg. 864-74
(Oct 2002)
ISSN: 0929-1903 England |
| PMID | 12224028
(Publication Type: Comparative Study, In Vitro, Journal Article)
|
| Chemical References |
- Antiviral Agents
- Ganciclovir
- Thyroglobulin
- Aspartate Aminotransferases
- Alanine Transaminase
- Thymidine Kinase
- beta-Galactosidase
|
| Topics |
- Adenoviridae
(genetics)
- Alanine Transaminase
(blood)
- Animals
- Antiviral Agents
(therapeutic use)
- Aspartate Aminotransferases
(blood)
- Cell Division
- Ganciclovir
(therapeutic use)
- Gene Therapy
(methods)
- Genes, Reporter
- Genetic Vectors
- Haplorhini
- Humans
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Promoter Regions, Genetic
- Rats
- Simplexvirus
(enzymology)
- Tandem Repeat Sequences
(genetics)
- Thymidine Kinase
(genetics, pharmacology)
- Thyroglobulin
(genetics)
- Thyroid Neoplasms
(enzymology, pathology, therapy)
- beta-Galactosidase
(metabolism)
|
