This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nishihara, E. Articles by Yamashita, S. Search for Related Content PubMed PubMed Citation Articles by Nishihara, E. Articles by Yamashita, S.

Retrovirus-Mediated Herpes Simplex Virus Thymidine Kinase Gene Transduction Renders Human Thyroid Carcinoma Cell Lines Sensitive to Ganciclovir and Radiation in Vitro and in Vivo

Department of Nature Medicine, Atomic Bomb Disease Institute (E.J., H.N., S.Y.), Department of Pharmacology 1 (Y.N., K.T., M.N.), and First Department of Internal Medicine (H.M.), Nagasaki University School of Medicine, Nagasaki 852, Japan

Address all correspondence and requests for reprints to: Yuji Nagayama, M.D., Department of Pharmacology 1, Nagasaki University School of Medicine, Sakamoto 1–12-4, Nagasaki 852, Japan. E-mail: nagayama{at}net.nagasaki-u.ac.jp

In an attempt to develop gene therapy for thyroid carcinomas, the present studies were undertaken to evaluate in vitro and in vivo therapeutic efficacy and toxicity of herpes simplex virus thymidine kinase (HSV-tk) gene and ganciclovir (GCV) treatment, a widely used prodrug/suicide gene therapy, in human thyroid carcinoma cell lines, FRO and WRO cells, using a means of retrovirus-mediated gene transduction. In vitro experiments demonstrated dose- and time-dependent cell killing by transduction of the HSV-tk gene followed by GCV treatment. The IC₅₀ (the concentration required to elicit 50% growth inhibition) shifted from 250 to 0.5 mg/liter in FRO cells, and from 3,000 to 0.09 mg/liter in WRO cells with therapeutic indexes of 500 and 33,000, respectively. Treatment with 30 mg/liter GCV for 4 days led to complete cell death in HSV-tk tumor cells. Nontransduced cells mixed with transduced cells were also effectively killed by GCV (bystander effect). Low concentrations of GCV, which alone showed little cytotoxicity, enhanced radiation-induced cytotoxicity (radiosensitization). In vivo sc FRO-tk tumor models in nude mice also showed dose- and time-dependent tumor regression. The IC₅₀ was less than 2 mg/kg, and treatment with 100 mg/kg GCV for 2 weeks completely eradicated all tumors. The bystander effect and radiosensitization were also obtained in vivo. These results suggest that the HSV-tk/GCV approach to human thyroid carcinoma cells appears to be very efficacious, with a wide therapeutic range, and exerts a bystander effect and radiosensitization both in vitro and in vivo. Thus, HSV-tk/GCV system, alone or in combination with radiotherapy, may be a promising suicide gene therapy for thyroid carcinomas.

This article has been cited by other articles:

				R. E. Schweppe, J. P. Klopper, C. Korch, U. Pugazhenthi, M. Benezra, J. A. Knauf, J. A. Fagin, L. A. Marlow, J. A. Copland, R. C. Smallridge, et al. Deoxyribonucleic Acid Profiling Analysis of 40 Human Thyroid Cancer Cell Lines Reveals Cross-Contamination Resulting in Cell Line Redundancy and Misidentification J. Clin. Endocrinol. Metab., November 1, 2008; 93(11): 4331 - 4341. [Abstract] [Full Text] [PDF]

				A. Tomioka, M. Tanaka, M. A. De Velasco, S. Anai, S. Takada, T. Kushibiki, Y. Tabata, C. J. Rosser, H. Uemura, and Y. Hirao Delivery of PTEN via a novel gene microcapsule sensitizes prostate cancer cells to irradiation Mol. Cancer Ther., July 1, 2008; 7(7): 1864 - 1870. [Abstract] [Full Text] [PDF]

				M. Braga-Basaria and M. D. Ringel Beyond Radioiodine: A Review of Potential New Therapeutic Approaches for Thyroid Cancer J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 1947 - 1960. [Abstract] [Full Text] [PDF]

				B. S. Teh, E. Aguilar-Cordova, M. T. Vlachaki, L. Aguilar, W.-Y. Mai, J. Caillouet, M. Davis, B. Miles, D. Kadmon, G. Ayala, et al. Combining Radiotherapy with Gene Therapy (From the Bench to the Bedside): A Novel Treatment Strategy for Prostate Cancer Oncologist, October 1, 2002; 7(5): 458 - 466. [Abstract] [Full Text] [PDF]

				R. Zhang, F. H. Straus, and L. J. DeGroot Cell-Specific Viral Gene Therapy of a Hurthle Cell Tumor J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1407 - 1414. [Abstract] [Full Text] [PDF]

				E. M. Westphal, W. Blackstock, W. Feng, B. Israel, and S. C. Kenney Activation of Lytic Epstein-Barr Virus (EBV) Infection by Radiation and Sodium Butyrate in Vitro and in Vivo: A Potential Method for Treating EBV-positive Malignancies Cancer Res., October 1, 2000; 60(20): 5781 - 5788. [Abstract] [Full Text]

				Y. Nagayama, E. Nishihara, M. Iitaka, H. Namba, S. Yamashita, and M. Niwa Enhanced Efficacy of Transcriptionally Targeted Suicide Gene/Prodrug Therapy for Thyroid Carcinoma with the Cre-loxP System Cancer Res., July 1, 1999; 59(13): 3049 - 3052. [Abstract] [Full Text] [PDF]