This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted 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 Zhang, R. Articles by DeGroot, L. J. Search for Related Content PubMed PubMed Citation Articles by Zhang, R. Articles by DeGroot, L. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB GANCICLOVIR Medline Plus Health Information Genes and Gene Therapy Thyroid Cancer

Cell-Specific Viral Gene Therapy of a Hurthle Cell Tumor

Thyroid Study Unit (R.Z., J.D.), Department of Medicine, Department of Pathology (F.H.S.), The University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Leslie J. DeGroot, M.D., Thyroid Study Unit, Mail Code 3090, The University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637.

Abstract

We evaluated the effectiveness of a replication-defective adenovirus-transducing thymidine kinase (TK) gene under the control of the rat Tg (rTg) promoter (AdrTgtk) in therapy of a human Hurthle cancer (XTC-1 cell) in vitro and in vivo. The ganciclovir (GCV) sensitivity of infected XTC-1 cells was assessed in vitro by H³-thymidine incorporation assay and Trypan-blue exclusion, and by an in vivo tumor development assay. Proliferation was strongly inhibited by adding GCV into the culture medium of infected cells, but not uninfected cells, proving cell infection and expression of TK in the XTC-1 cells. AdrTgtk, and also viruses that have the noncell-specific cytomegalovirus (CMV) promoter-directing expression of TK (AdCMVtk), or luciferase (AdCMVLuc), were used to transduce XTC-1 cells to evaluate killing effects. After infection with AdCMVtk or AdrTgtk, followed by GCV treatment, 70% of infected cells were killed in the presence of GCV, compared with less than 20% of cells infected by AdCMVLuc and treated with GCV.

In vivo toxicity was studied in BALB/c mice. When adenovirus is given iv, liver is the major organ infected. No significant changes of the serum transaminase levels and no histological abnormalities were found in animals treated with AdrTgtk/GCV given iv, compared with control animals. High levels of serum transaminases, lymphocyte infiltration, some Kupffer’s cell prominence, and extensive single-cell hepatocyte death were found in AdCMVtk/GCV-treated animals, indicating severe liver damage induced, as expected, by the noncell-specific CMV promoter.

XTL-1 cells (2 x 10⁶) were injected sc into BALB/c-severe combined immunodeficient mice (BALB/c-SCID), and the mice developed tumors after 3 wk. After intratumoral injection of AdrTgtk and treatment with GCV, tumors stabilized in 15 of 17 mice within 3 wk, 9 tumors remained stabilized after 5 wk of treatment, and 2 disappeared during observation. In AdCMVLuc/GCV-treated control mice, almost all tumors grew continuously. The average tumor size in AdrTgtk-treated mice was significantly smaller than that of control animals after 2 wk of treatment.

Our data confirm the effectiveness and specificity of an adenovirus using rTg promoter to express TK, and support its future application to thyroid cancer gene therapy in humans.

This article has been cited by other articles:

				S. Kesmodel, I. Prabakaran, R. Canter, C. Menon, K. Molnar-Kimber, and D. Fraker Virus-Mediated Oncolysis of Thyroid Cancer by a Replication-Selective Adenovirus Driven by a Thyroglobulin Promoter-Enhancer Region J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3440 - 3448. [Abstract] [Full Text] [PDF]

				L. Barzon, M. Boscaro, and G. Palu Endocrine Aspects of Cancer Gene Therapy Endocr. Rev., February 1, 2004; 25(1): 1 - 44. [Abstract] [Full Text] [PDF]

				E. L. Davies, J. D. Ramsden, H. Cocks, P. F. Searle, J. C. Watkinson, H. Ueno, A. Logan, J. A. Franklyn, V. Mautner, and M. C. Eggo Adenovirus-Mediated Expression of Dominant Negative Fibroblast Growth Factor (FGF) Receptor 1 in Thyroid Cells Blocks FGF Effects and Reduces Goitrogenesis in Mice J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4472 - 4480. [Abstract] [Full Text] [PDF]