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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 8 3531-3538
Copyright © 2003 by The Endocrine Society

Tumor-Specific Gene Therapy for Undifferentiated Thyroid Carcinoma Utilizing the Telomerase Reverse Transcriptase Promoter

Teiji Takeda, Hidehumi Inaba, Masanori Yamazaki, Satoru Kyo, Takahide Miyamoto, Satoru Suzuki, Takashi Ehara, Tomoko Kakizawa, Masahiro Hara, Leslie J. DeGroot and Kiyoshi Hashizume

Department of Aging Medicine and Geriatrics (T.T., H.I., T.M., S.S., T.K., M.H., K.H.), Shinshu University, Graduate School, Matsumoto, Nagano 390-8621, Japan; Thyroid Study Unit (M.Y., L.D.G.), Department of Medicine, University of Chicago, Chicago, Illinois 60637; Department of Obstetrics and Gynecology (S.K.), Kanazawa University, School of Medicine, Kanazawa, Ishikawa 920-0934, Japan; and Department of Pathology (T.E.), Shinshu University, School of Medicine, Matsumoto, Nagano 390-8621, Japan

Address all correspondence and requests for reprints to: Teiji Takeda, M.D., Ph.D., Department of Aging Medicine and Geriatrics, Shinshu University, Graduate School, 3-1-1 Asahi Matsumoto-city, Nagano-prefecture 390-8621, Japan. E-mail: teiji{at}hsp.md.shinshu-u.ac.jp.

A tumor-specific targeting system for cancer gene therapy was studied using the human telomerase reverse transcriptase (hTERT) promoter. Telomerase activity is increased in most tumors but not detected in most normal cells. We developed the recombinant adenovirus, carrying human herpes simplex virus thymidine kinase gene under the control of the hTERT promoter (AdhTERTtk) to obtain restricted expression of a suicide gene only in tumor cells. We found that transcriptional activity of hTERT was 2- to 9-fold higher in undifferentiated thyroid carcinoma cell lines than that of the Simian virus 40 promoter in transient transfection assay. Undifferentiated thyroid carcinoma cell lines were infected with AdhTERTtk, and sensitivity to ganciclovir (GCV) was analyzed. Cell viability was decreased in a GCV dose-dependent manner after treatment with AdhTERTtk/GCV. The cell-killing ability of AdhTERTtk in all thyroid or nonthyroid carcinoma cell lines tested was similar to AdCMVtk, which carries herpes simplex virus thymidine kinase gene driven by the cytomegalovirus promoter. However, normal cell lines were largely unaffected by AdhTERTtk/GCV, whereas these cells were also sensitive to GCV after infection with AdCMVtk. A xenograft model was established by transplanting human differentiated or undifferentiated thyroid carcinoma cells into Balb-C nude mice. The injections of AdhTERTtk into tumors and ip administration of GCV showed significant inhibition of tumor growth, similar to AdCMVtk/GCV treatment. Systemic administrations of adenovirus and GCV to normal rats demonstrated remarkable increase of serum liver transaminase levels and severe hepatic damages in pathological examinations in AdCMVtk-injected rats but not in the AdhTERTtk group. These results indicate that the AdhTERTtk/GCV system is a promising therapy for undifferentiated thyroid carcinoma, which is one of the most malignant tumors, without damage to normal tissues.

Abbreviations: ß-gal, ß-Galactosidase; BW, body weight; CMV, cytomegalovirus; FBS, fetal bovine serum; GCV, ganciclovir; GOT, glutamic oxaloacetic transaminase; GPT, glutamic pyruvic transaminase; 6H, six hormones or growth factors; HSVtk, human herpes simplex virus thymidine kinase; hTERT, human telomerase reverse transcriptase; MOI, multiplicity of infection; PCSM, penicillin and streptomycin; pfu, plaque-forming units; TG, thyroglobulin; TK, thymidine kinase; UTC, undifferentiated thyroid carcinoma.




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