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

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 IC 50 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.