Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid carcinoma accounts for the majority of deaths from endocrine cancers. Although effective therapies exist for well differentiated tumors, the treatment options for poorly differentiated and anaplastic tumors are much less effective. In the present study we demonstrate that the thyroglobulin (Tg) promoter can be used to direct specific expression of either luciferase or thymidine kinase in thyroid cancer cells. Furthermore, using a putative enhancer element for the Tg gene, the activity of the Tg promoter in and its specificity for thyroid cells were enhanced. In transient transfectants or in stably transfected thyroid carcinoma cells, treatment with the histone deacetylase inhibitors, depsipeptide (FR9012228) and sodium butyrate, alone or in combination with 8-bromo-cAMP, resulted in further enhancement. In experiments in which the herpes simplex virus thymidine kinase (HSV-TK) gene was driven by the Tg promoter and the putative enhancer, HSV-TK expression and ganciclovir sensitivity were augmented. Similar results were obtained in two cell lines derived from a follicular thyroid carcinoma and in two anaplastic thyroid carcinoma cell lines. In summary, we report the construction of a suicide HSV-TK vector with preferential toxicity for thyroid cells. The results in anaplastic thyroid carcinoma cells suggest that it may be of use in the full spectrum of thyroid malignancies.
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PMID:Construction of gene therapy vectors targeting thyroid cells: enhancement of activity and specificity with histone deacetylase inhibitors and agents modulating the cyclic adenosine 3',5'-monophosphate pathway and demonstration of activity in follicular and anaplastic thyroid carcinoma cells. 1115 54

A replication defective adenovirus transducing thymidine kinase (TK) gene under the control of the rat thyroglobulin (rTg) promoter (AdrTgtk) was developed to evaluate its cell-specific killing activity in gene therapy. We also developed adenoviruses containing the TK gene driven by the cytomegalovirus (CMV) promoter (AdCMVtk), and luciferase (Luc) gene driven by the rTg or CMV promoter (AdrTgLuc or AdCMVLuc). Luc activity in FRTL-5, HepG2, COS1, rMTC, hMTC, Hela, GH3, T98G, and CA77 cells was measured after infection with AdrTgLuc or AdCMVLuc. FRTL-5 cells produce thyroglobulin (Tg), whereas all other cells are non-Tg-producing cell lines. Transduction by AdCMVLuc caused high Luc activity in all cell lines. However, infection with AdrTgLuc induced Luc activity only in FRTL-5 cells. AdCMVtk or AdrTgtk was used to transduce various cell lines to evaluate the different killing effect. After infection with AdCMVtk vector followed by ganciclovir (GCV) treatment, cell growth was strongly suppressed in all cell lines compared both to noninfected cells and to cells infected by AdCMVLuc in the presence of GCV. When FRTL-5 cells were infected with AdrTgtk followed by GCV treatment, more than 90% were killed, but only a minimal effect was observed in other cell lines, indicating that the Tg promoter transduced TK expression only in Tg-producing cells. When adenovirus is given intravenously, liver and spleen are the major organs infected. A high Luc activity was found in liver and spleen of AdCMVLuc treated animals. No Luc activity was found in liver and spleen of AdrTgLuc-treated animals, indicating that rTg does not transduce Luc expression in non-Tg-producing tissues in vivo. No significant changes of the serum transaminase levels and histologic abnormalities were found in animals treated with AdrTgtk/GCV compared with control animals. High levels of serum transaminases, lymphocyte infiltration, some Kupffer's cell prominence, and extensive single cell hypatocyte death were found in AdCMVtk/GCV-treated animals, indicating severe liver damage induced, as expected, by a noncell-specific promoter. These results indicate that transfer of TK gene driven by the rTg promoter has thyroid cell-specific killing ability in the presence of GCV, little in vivo toxicity, and should be useful in the future for treating thyroid Tg-producing cancers.
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PMID:Adenoviral-mediated gene therapy for thyroid carcinoma using thymidine kinase controlled by thyroglobulin promoter demonstrates high specificity and low toxicity. 1128 80

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 x TGtk) to obtain thyroid-specific cell killing ability. The transduction of HSVtk genes by infection with Ad2 x 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 x 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 x TGtk and AdTGtk needed more than 100-fold concentrated GCV to reach IC(50) compared to AdCMVtk. We confirmed the enhanced efficacy of Ad2 x TGtk for tissue-specific cytotoxicity in vivo. After adenovirus/GCV treatment for FTC-133 tumor-bearing nude mice, Ad2 x TGtk enhanced tumor growth inhibition and survival rates compared to AdTGtk. Tumor growth inhibition and survival rates by Ad2 x TGtk were similar to that by AdCMVtk. Moreover, any toxic effect for rat normal tissues was not revealed after intravenous injections with Ad2 x 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 x TGtk for tissue-specific gene therapy for TG-producing thyroid carcinomas without toxicity for normal tissues.
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PMID:A tandemly repeated thyroglobulin core promoter has potential to enhance efficacy for tissue-specific gene therapy for thyroid carcinomas. 1222 28

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 (beta-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.
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PMID:Transcriptionally targeted retroviral vector for combined suicide and immunomodulating gene therapy of thyroid cancer. 1241 7

Thyroid cancers are of special interest in gene therapy, since it is possible to direct gene expression specifically to the thyroid derived cells by using promoters with limited expression, and secondly, because destruction of the normal tissue by introduction of a toxic gene would have no important adverse effect. A variety of methods for gene delivery are available. Adenovirus is a well studied and widely used vector and is useful for targeting genes because it infects many cell types, including differentiated thyroid cancer and medullary thyroid cancer cells. Strategies that have been employed successfully in animal models include adenoviral mediated expression of thymidine kinase under control of a thyroglobulin promoter, similarly expression of the cytokine IL-2, and perhaps most effectively, expression of IL-12. Combinations of vectors expressing thymidine kinase and IL-12 under control of a strong but non-tissue specific CMV promoter effectively destroy a model anaplastic thyroid tumor in Wistar rats. Replicating adenoviruses, in contrast to the non-replicating form commonly used, have also been used to infect tumor cells and express P-53 protein, leading to apoptosis of tumor cells. Medullary thyroid cancer provides a target much like differentiated thyroid cancer because it is possible to address gene expression specifically to the medullary thyroid cells by the use of a modified calcitonin promoter. Animal models of this tumor are available in a mouse and Wag/Rij rat model. In the latter system, treatment with adenoviruses expressing genes under control of the modified calcitonin promoter and expressing thymidine kinase or IL-12 leads to destruction of growing medullary thyroid cancer tumors, destroy distant tumors after injection in one tumor, and cause induction of long lasting immunity to subsequent tumor development in the animals. There are many ongoing studies of gene therapy in humans using various genes such as thymidine kinase, IL-2, and now IL-12. Although none of these trials to date shows complete eradication of metastatic tumors in humans, there are reports showing distinctly that the viral mediated gene therapy approach can effectively destroy human tumors after in vivo administration. Tumors that have been treated include melanomas, glioblastomas, breast tumors, and prostate carcinomas. In the latter studies, it has been possible to show objective responses documented by a fall in serum PSA levels of 50% or more that are sustained for prolonged periods. Gene therapy using the adenoviral vectors appears to be safe in studies reported so far. A problem is prior or induced immunity to adenoviral proteins, but direct injection of the vector into a tumor nodule largely circumvents this problem. New genes and new vectors under development will certainly lead to the established use of these methods in the therapy of human thyroid carcinomas in the near future.
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PMID:Viral mediated gene therapy for the management of metastatic thyroid carcinoma. 1537 25


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