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

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
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 9 Issue 10 Pg. 864-74 (Oct 2002) ISSN: 0929-1903 [Print] England
• PMID: 12224028 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antiviral Agents
• Thyroglobulin
• Aspartate Aminotransferases
• Alanine Transaminase
• Thymidine Kinase
• beta-Galactosidase
• Ganciclovir

Topics

• Adenoviridae (genetics)
• Alanine Transaminase (blood)
• Animals
• Antiviral Agents (therapeutic use)
• Aspartate Aminotransferases (blood)
• Cell Division
• Ganciclovir (therapeutic use)
• Genes, Reporter
• Genetic Therapy (methods)
• Genetic Vectors
• Haplorhini
• Humans
• In Vitro Techniques
• 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)