Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We examined whether antitumor effect could be produced by retrovirally expressed interleukin-2(IL-2) gene, glanulocyte macrophage-colony stimulating factor(GM-CSF) gene, herpes simplex virus-thymidine kinase(HSV-tk) gene and p53 gene in human esophageal cancer cells using nude mice. Loss of tumorigenicity of IL-2 or GM-CSF producing cancer cells were observed. The antitumor effect was also evidenced by the injection of these cells into established tumors of wild-type cells. In suicide gene therapy on esophageal cancer, the growth suppression of esophageal cancer cells transducing HSV-tk gene tumors in nude mice induced by ganciclovir treatment and all the tumors disappeared. The wild-type p53 transduced tumor cells became markedly susceptible to irradiation and anticancer agents. Administration of cisplatine noticeably suppressed the growth of p53 transduced tumors inoculated in nude mice. We established the clinical protocol of gene therapy for esophageal cancer using wild-type p53 gene with adenovirus vector. In this autumn we are going to start this clinical trial.
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PMID:[The protocol of clinical trial and basic experiments for esophageal cancer using gene transduction]. 1100 29

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

In augmenting systemic anti-tumor immune response, the authors evaluated the genetic modification of Ewing family tumor (EFT) cell lines for use as allogeneic vaccines. EFT cell lines A673 and RD-ES were transfected with cDNAs for human interleukin (IL)-2 and/or HSV1 thymidine kinase (HSV1-tk), respectively. Clones with high and stable secretion of IL-2 alone or with coexpression of functional HSV1-tk were obtained and their features were analyzed. IL-2 expressing clones derived from the A673 cell line demonstrated decreased expression of HLA class I molecules compared with the parental cell line and corresponding clones derived from RD-ES. However, IFN-gamma could upregulate the expression of HLA class I antigens by IL-2 transfected A673 cells. Ganciclovir induced apoptosis in double-transfected cell clones. IL-2/HSV1-tk cells continued to produce and release IL-2 after initial ganciclovir treatment. After gamma-irradiation, transfected clones released bioactive IL-2 in a quantity sufficient to activate T and natural killer cells in culture. A polyvalent allogeneic vaccine was also obtained using fusion of two different transgenic cell lines. The resulting hybrids inherited antigenic and transgenic characteristics of both parental cell lines. It is presumed that the cell lines generated here could be used as allogeneic vaccines for treatment of patients with EFTs.
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PMID:Stable transgenic expression of IL-2 and HSV1-tk by single and fusion tumor cell lines bearing EWS/FLI-1 chimeric genes. 1255 23

Proper antigen presentation is paramount to the induction of effective and persistent antitumor immune responses. In a murine model of hepatic metastasis of colon cancer, we found that the numbers of in situ mature dendritic cells (DCs) and macrophages in tumor-infiltrating leukocytes (TILs) were significantly increased in mice treated with the combination therapy of herpes simplex virus thymidine kinase, interleukin 2, and GM-CSF genes when compared with control groups without GM-CSF treatment. Significantly higher levels of IFN-gamma, MIP-1 alpha, mIL-12, and GM-CSF were detected in the tumor after the combination therapy. T cells isolated from the combination therapy-treated mice exhibited higher ex vivo direct CTL activity than those from other treatment groups. Antigen-presenting cells (APCs) enriched from the TILs and liver of the combination therapy-treated mice induced higher levels of proliferation by the splenocytes from long-term surviving mice that had been cured of tumors at early time points (days 4 and 7) whereas significant APC activity was only observed in the spleen at the latter time point (day 7, 14) after the combination therapy. In contrast, APCs isolated from tk or tk + IL-2-treated mice did not induce any significant proliferation. Subcutaneous injection of fluorescence-labeled latex microspheres followed by the combination therapy showed a similar sequential trafficking of microspheres, day 4 after the combination therapy to tumor and day 14 to spleen. The results suggest that APCs recruited by intratumoral gene delivery of GM-CSF can capture antigens, mature to a stage suitable for antigen presentation, and subsequently migrate to the spleen where they can efficiently stimulate antigen-specific T cells.
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PMID:In situ recruitment of antigen-presenting cells by intratumoral GM-CSF gene delivery. 1295 80

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

IL-2 is an important cytokine that is capable of inducing both proliferation and apoptosis of activated T cells. CD4 T cells are thought to be the major producers of IL-2, but CD8 T cells also produce copious amounts of this cytokine. However, our current understanding regarding the kinetics of IL-2 production by antigen-specific CD8 T cells, and the proportion of these cells that produce IL-2 in vivo, is extremely limited. We now demonstrate that virus-specific CD8 T cells initiate IL-2 production by 6 h post-infection and prior to cell division in vivo. Interestingly, peak levels of IL-2 production were achieved very early during the response and prior to the proliferative peak. We also show -- using transgenic mice expressing herpes simplex virus-1 thymidine kinase under the control of the IL-2 promoter -- that, unlike what has been reported for antigen-specific CD4 T cells, the majority of antigen-specific CD8 T cells produce IL-2 during primary as well as secondary immune responses in vivo.
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PMID:Frontline: An in-depth evaluation of the production of IL-2 by antigen-specific CD8 T cells in vivo. 1538 78

This study represents the first report of gene therapy for anaplastic thyroid carcinoma, one of the most aggressive solid tumors in humans. Two patients with end-stage anaplastic thyroid carcinoma were treated by direct intratumor injection of retroviral vector producer cells followed by ganciclovir. The retroviral vector carried the human IL-2 gene and the suicide gene thymidine kinase of herpes simplex virus type 1. Treatment was safe and associated with only mild adverse events. Transduction of tumor cells and production of T helper type 1 cytokines was demonstrated in tumor biopsies. Gene therapy led also to a marked increase in T helper type 1 cytokine expression in peripheral blood mononuclear cells. Radiological evaluation of injected tumor masses demonstrated local tumor necrosis.
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PMID:A pilot study of combined suicide/cytokine gene therapy in two patients with end-stage anaplastic thyroid carcinoma. 1571 4

Mesothelioma may be particularly well suited for gene therapy treatment owing to its accessibility, allowing both intrapleural and intratumoral gene delivery. At least four gene therapy trials have been carried out in mesothelioma patients, using different vector systems (adenovirus, vaccinia virus, irradiated tumor cells), and different transgenes (herpes simplex virus thymidine kinase (HSVtk) combined with ganciclovir, IL-2, IFN-beta). Although small in scale, these trials have given an inkling of hope for therapeutic efficacy. However, it is clear that gene therapy protocols need to be optimized further. This paper will review progress made in (i) vector development, (ii) defining optimal transgenes, and (iii) gene delivery. Adenoviruses are the most commonly used vectors for gene therapy, and are continuously being improved. With respect to the nature of the transgenes, five categories can be distinguished: (i) 'suicide' or sensitivity genes (e.g., HSVtk), (ii) cytokines and other immune modulators, (iii) replacements for mutant tumor suppressor genes (e.g., p53), (iv) antiangiogenic proteins and (v) tumor antigens. It seems clear that expression of a single transgene is unlikely to be sufficient to eradicate a tumor, such as mesothelioma, that is diagnosed late in disease progression. Hence, multimodality therapy, including conventional therapy (chemo- and radiotherapy, surgery) with one or more transgenes has a higher chance of success.
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PMID:Gene therapy for malignant mesothelioma: beyond the infant years. 1643 92

The production, manipulation and rescue of a bacterial artificial chromosome clone of Vaccinia virus (VAC-BAC) in order to expedite construction of expression vectors and mutagenesis of the genome has been described (Domi & Moss, 2002, PNAS99 12415-20). The genomic BAC clone was 'rescued' back to infectious virus using a Fowlpox virus helper to supply transcriptional machinery. We apply here a similar approach to the attenuated strain Modified Vaccinia virus Ankara (MVA), now widely used as a safe non-replicating recombinant vaccine vector in mammals, including humans. Four apparently full-length, rescuable clones were obtained, which had indistinguishable immunogenicity in mice. One clone was shotgun sequenced and found to be identical to the parent. We employed GalK recombination-mediated genetic engineering (recombineering) of MVA-BAC to delete five selected viral genes. Deletion of C12L, A44L, A46R or B7R did not significantly affect CD8(+) T cell immunogenicity in BALB/c mice, but deletion of B15R enhanced specific CD8(+) T cell responses to one of two endogenous viral epitopes (from the E2 and F2 proteins), in accordance with published work (Staib et al., 2005, J. Gen. Virol.86, 1997-2006). In addition, we found a higher frequency of triple-positive IFN-gamma, TNF-alpha and IL-2 secreting E3-specific CD8+ T-cells 8 weeks after vaccination with MVA lacking B15R. Furthermore, a recombinant vaccine capable of inducing CD8(+) T cells against an epitope from Plasmodium berghei was created using GalK counterselection to insert an antigen expression cassette lacking a tandem marker gene into the traditional thymidine kinase locus of MVA-BAC. MVA continues to feature prominently in clinical trials of recombinant vaccines against diseases such as HIV-AIDS, malaria and tuberculosis. Here we demonstrate in proof-of-concept experiments that MVA-BAC recombineering is a viable route to more rapid and efficient generation of new candidate mutant and recombinant vaccines based on a clinically deployable viral vector.
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PMID:Recombination-mediated genetic engineering of a bacterial artificial chromosome clone of modified vaccinia virus Ankara (MVA). 1828 94

The poor prognosis for patients with aggressive or metastatic tumors and the toxic side effects of currently available treatments necessitate the development of more effective tumor-selective therapies. Stem/progenitor cells display inherent tumor-tropic properties that can be exploited for targeted delivery of anticancer genes to invasive and metastatic tumors. Therapeutic genes that have been inserted into stem cells and delivered to tumors with high selectivity include prodrug-activating enzymes (cytosine deaminase, carboxylesterase, thymidine kinase), interleukins (IL-2, IL-4, IL-12, IL-23), interferon-beta, apoptosis-promoting genes (tumor necrosis factor-related apoptosis-inducing ligand) and metalloproteinases (PEX). We and others have demonstrated that neural and mesenchymal stem cells can deliver therapeutic genes to elicit a significant antitumor response in animal models of intracranial glioma, medulloblastoma, melanoma brain metastasis, disseminated neuroblastoma and breast cancer lung metastasis. Most studies reported reduction in tumor volume (up to 90%) and increased survival of tumor-bearing animals. Complete cures have also been achieved (90% disease-free survival for >1 year of mice bearing disseminated neuroblastoma tumors). As we learn more about the biology of stem cells and the molecular mechanisms that mediate their tumor-tropism and we identify efficacious gene products for specific tumor types, the clinical utility of cell-based delivery strategies becomes increasingly evident.
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PMID:Stem and progenitor cell-mediated tumor selective gene therapy. 1836 24


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