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 Barzon, L. Articles by Palù, G. Search for Related Content PubMed PubMed Citation Articles by Barzon, L. Articles by Palù, G.

Transcriptionally Targeted Retroviral Vector for Combined Suicide and Immunomodulating Gene Therapy of Thyroid Cancer

Department of Histology, Microbiology, and Medical Biotechnologies (L.B., R.B., I.C., E.G., C.P., G.P.), University of Padova, I-35121 Padova; Department of Pathology (M.C.), University of Verona, I-37134 Verona; and Department of Internal Medicine (M.B.), University of Ancona, I-60100 Ancona, Italy

Address all correspondence and requests for reprints to: Giorgio Palù, M.D., Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, Via Gabelli 63, I-35121 Padova, Italy. E-mail: giorgio.palu{at}unipd.it.

Abstract

Gene therapy may be an effective approach to thyroid carcinoma refractory to conventional treatment. A transcriptionally targeted retroviral vector for gene therapy of thyroid carcinomas was generated replacing the viral enhancer with the enhancer sequence of the human thyroglobulin (TG) gene, yielding a chimeric long-terminal repeat. The TG enhancer was used to drive the expression of either a reporter gene (ß-galactosidase) or two therapeutic genes, i.e. the prodrug-activating enzyme thymidine kinase of herpes simplex virus (HSV-TK) and human IL-2, separated by an internal ribosome entry site. The corresponding vector having an unmodified long-terminal repeat was used as control. The targeted vector allowed selective transgene expression and cell killing in differentiated thyroid tumor cells but not in anaplastic thyroid carcinoma cells and nonthyroid cells, as demonstrated by quantitative RT-PCR and cytotoxicity assays. Nude mice injected with tumor cells underwent near complete or complete regression of tumors transduced with the control vector after ganciclovir treatment. On the other hand, infection with the thyroid-specific vector led to regression only of TG-expressing tumors. In addition, tumors expressing human IL-2 showed significant growth retardation, compared with nontransduced tumors while exhibiting signs of necrosis and presence of an inflammatory infiltrate. However, HSV-TK/IL-2 plus ganciclovir was significantly more efficient than HSV-TK/IL-2 alone in eradicating tumor masses. Our results indicate that replacement of viral enhancer with TG enhancer confers selectivity of transgene expression in thyroid cells. Thus, the combined thyroid-specific expression of two therapeutic genes (cytokine and suicide genes), although a safe tumor-targeted treatment, would allow an increased anticancer effect.

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. Pacenti, A. Taccaliti, E. Franchin, M. Bruglia, M. Boscaro, and G. Palu A Pilot Study of Combined Suicide/Cytokine Gene Therapy in Two Patients with End-Stage Anaplastic Thyroid Carcinoma J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2831 - 2834. [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]