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)

Expression of suicide genes (e.g. herpes simplex virus thymidine kinase,HSV-TK) in T cells is an appealing approach to regulate graft-versus-host disease in adoptive immunotherapy. Here we report the optimization of retroviral infection of canine T cells. Canine T cells were stimulated either with phytohemagglutinin (PHA, 2 microg/ml) for 24-72 hours or with 100 U/ml interleukin-2 for seven days. Stimulated cells were co-cultivated with irradiated virus-producing cells. Transduction efficiencies ranged from 4% to 45% using PG13, a gibbon ape leukemia virus envelope (env) pseudotyped packaging cell line. Infection of cells with GPenvAM12, expressing the amphotropic Moloney murine leukemia virus env, did not yield a satisfactory percentage of transduced cells. Enrichment of transduced cells was performed using immunoselection, and gave a purity of up to 98%. Transfusion of 1 x 10(6) transduced cells per kilogram body weight showed that transduced cells could convert mixed chimerism to 100% and transfer immunity to a specific antigen. Transduced cells were repeatedly detected in peripheral blood and bone marrow by polymerase chain reaction with primers specific for the HSV-TK gene. We have demonstrated the feasibility of using the canine model to study gene therapy as a preclinical model.
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PMID:Expression of HSV-TK suicide gene in primary T lymphocytes: the dog as a preclinical model. 1097 36

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

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality of allogeneic stem cell transplantation. Strategies to control GVHD while maintaining graft versus leukemia (GVL) include herpes simplex virus thymidine kinase (HSV-tk) gene transduction of donor T cells followed by treatment with ganciclovir (GCV). Alternatively, GVHD and GVL may be mediated by distinct processes. In this regard, whether cytokine polarization occurs and to what degrees various subsets of cytokine-producing T cells mediate GVHD or GVL has been an active area of research using cytokine or cytokine antibody infusion or genetically deficient mice. This study takes a different approach that allows simultaneous investigation into both the mechanisms underlying GVHD reactions and the efficacy of HSV-tk suicide gene-based T-cell deletion. A source of donor T cells, splenocytes from mice transgenic for HSV-tk controlled by elements of either the interleukin-2 (IL-2) or IL-4 promoters (IL-2-tk and IL-4-tk, respectively) was used, thus allowing investigation into the roles of T1 and T2 cells in ongoing GVHD reactions. To assess treatment rather than prevention of GVHD, GCV was started at peak disease. Remarkably, treatment at this late time point rescued mice from the clinical effects of GVHD caused by T cells expressing either transgene. Thus, both T1 and T2 cells play an important role in clinical GVHD in a minor histocompatibility antigen-mismatched setting. In addition, because clinical disease was reversible even at its maximum, these observations provide controlled evidence that this strategy of treating ongoing GVHD could be effective clinically.
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PMID:Selective T-cell subset ablation demonstrates a role for T1 and T2 cells in ongoing acute graft-versus-host disease: a model system for the reversal of disease. 1171 76

To explore a more efficient multi-gene antitumor treatment, we developed an adenoviral vector expressing both herpes simplex virus thymidine kinase (HSVtk) and human interleukin-2 (hIL-2) (AdCMVTKhIL2). Production of hIL-2 is expected to augment antitumor T cell and natural killer cell activity. Two separate cassettes expressing HSVtk and hIL-2, each under the control of the human cytomegalovirus (CMV) immediate early gene promoter, were inserted into the early 1 region of adenovirus type 5. This vector showed similar direct cytotoxicity towards infected rat medullary thyroid carcinoma (rMTC) cells as did the single gene vector, AdCMVtk. rMTC cells infected with the virus in vitro showed high sensitivity to ganciclovir. After infection with AdCMVTKhIL2 at 100 m.o.i. for 1 h, more than 20 000 U hIL-2 were produced during 24 h by 1 &times 10(6) rMTC cells on day 2 and day 3. hIL-2 was also detected in the supernatants of primary cultures from tumors treated in vivo by the AdCMVTKhIL2 vector. Infected cells lost their tumorigenicity when transplanted subcutaneously into syngeneic rats, whereas all control animals developed tumors. More than 63% of tumors (19 out of 30 treated tumors) were destroyed when AdCMVTKhIL2 was injected intratumorally, compared with 38% when tumors were treated with AdCMVIL2, and 12% when treated with AdCMVtk, indicating an antitumor effect superior to that of each single vector given alone at the same dosage. These results indicate that the AdCMVTKhIL2 vector efficiently produces both HSVtk and hIL-2, and provides an enhanced antitumor activity.
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PMID:An adenoviral vector expressing functional heterogeneous proteins herpes simplex viral thymidine kinase and human interleukin-2 has enhanced in vivo antitumor activity against medullary thyroid carcinoma. 1173 28

Gene therapy for cancer using suicide genes such as the herpes simplex virus thymidine kinase gene (HSVtk) has been explored extensively in preclinical and clinical studies. We have improved the use of HSVtk by combining it with two cytokine genes encoding granulocyte/macrophage-colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2), and determined their additive/synergistic effects on tumor regression and inhibition of metastases in the non-immunogenic, spontaneously metastatic mammary tumor model, 4T1. Two adenoviral vectors (AV) were constructed, one carrying HSVtk (AV-TK) and the second (AV-GM/IL2) carrying Gm-CSf and Il2. Only the combination of AV-TK/GCV and AV-GM/IL2 showed a significant decrease in tumor growth and reduction of distant metastases with 25% of the tumors undergoing complete regression. When surgical excision of primary tumors was included in the regimen, local treatment with AV-TK/GCV plus AV-GM/IL2 further enhanced long-term survival. A fraction of the treated mice developed anti-tumor immunity and survived a second challenge with 4T1. Functional analyses demonstrated infiltration of lymphocytes within the tumor and a strong tumor-specific cytotoxic T lymphocyte response in TK- plus cytokine-treated animals. These data indicate that the coexpression of GM-CSF and IL-2 can augment the effect of HSVtk suicide gene therapy.
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PMID:Development of anti-tumor immunity against a non-immunogenic mammary carcinoma through in vivo somatic GM-CSF, IL-2, and HSVtk combination gene therapy. 1240 61

From mouse (C57BL/6) HPV-16 transformed cells denoted MK16/1/IIIABC (MK16) a cellular thymidine kinase deficient (cTK-) cell line was isolated. These cTK- cells were transduced by bicistronic recombinant adeno-associated viruses (rAAV) carrying the herpes simplex virus thymidine kinase gene and the gene for either the mouse granulocyte-macrophage colony stimulating factor (GM-CSF) or mouse interleukin-2 (IL-2). Transduced cells were highly sensitive to minute amounts of ganciclovir (GCV) and synthesized moderate amounts of the respective cytokines. A number of cell clones were tested for the cytokine production. The two best producer cell lines, the GM-CSF-producing cells denoted B9 and the IL-2-producing cells denoted 181, were selected for further experiments. Neither B9 nor 181 cells were tumorigenic in syngeneic animals. As inducers of antitumour immunity against challenge with MK16 cells, B9 cells proved superior to the 181 cells. GCV treatment did not markedly influence the level of immunity induced.
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PMID:Immunization with live HPV-16-transformed mouse cells expressing the herpes simplex thymidine kinase and either GM-CSF or IL-2. 1288 17

Retrovirally expressed interleukin-2 gene, granulocyte macrophage-colony stimulating factor gene, herpes simplex virus-thymidine kinase gene and p53 gene in human esophageal cancer cells showed antitumor effects in a nude mice xenotransplant model. We established a clinical protocol of gene therapy for advanced esophageal cancer using the wild type p53 gene with an adenovirus vector. In December of 2000, we began the first tumor suppressor gene therapy trial. Now, this trial, which has 9 patients. There have been no serious adverse event excluding fever and local pain. The feasibility of this treatment appears fairly good in these 9 cases. Furthermore, we developed a new method for transducing genes without a virus vector since a virus vector has several potentially unwanted properties. In vivo electroporation is a useful strategy for cancer gene therapy. Moreover, electric pulse to established solid tumors increases intracellular concentrations of chemotherapeutic agents. Transduction of the wild-type p53 gene by electroporation decreased the amount of nedaplatin required for tumor suppression. Electrochemo-gene therapy is a relatively simple method and can produce a better therapeutic effect.
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PMID:[Progress of gene therapy for esophageal cancer in Japan]. 1289 8

The incidence of prostate cancer has dramatically increased worldwide in the past decade, with mortality rates also increasing in many countries. Once prostate cancer is diagnosed, it is important to rapidly begin a treatment regimen that is either potentially curative or impedes disease progression. When the disease is confined to the prostate, it can be cured by radical prostatectomy or irradiation therapy. However, there are no curative therapies for locally advanced, recurrent, or metastatic diseases. Clearly, new therapies are needed for these patients. Gene therapy may provide additional therapeutic options with the potential to affect both localized and metastatic disease. Virus-mediated transduction of the herpes simplex virus thymidine kinase (HSV-tk) gene transfer, followed by a course of the prodrug ganciclovir (GCV), so-called suicide gene therapy, has been demonstrated by several investigators. The present in situ gene therapy clinical trial for human prostate cancer demonstrated safety, clinical efficacy, and biological effects of antitumor activity. HSV-tk clinical trials for prostate cancer are also ongoing in Japan, the Netherlands, and Mexico. Currently, numerous preclinical studies have reported immunomodulatory cytokine gene therapy, such as interleukin-2, interleukin-12, B7-1 (CD80), B7-2 (CD86) and granulocyte-macrophage colony-stimulating factor. Several clinical studies have been approved that potentially will show that these immunomodulatory gene therapies may generate an effective local and systemic antitumor activity and that should provide options for patients with prostate cancer. We review the multiple issues involved in current in situ gene therapy (gene/immunotherapy), its outcome, and future directions for patients with prostate cancer.
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PMID:In situ gene therapy for prostate cancer. 1563 15

We evaluated the safety, efficacy and anti-tumor effects of a surgery adjuvant treatment on canine patients with malignant melanoma. This approach combined suicide gene therapy with a subcutaneous vaccine composed by formolized tumor cells and irradiated xenogeneic cells producing human interleukin-2 and granulocyte-macrophage colony-stimulating factor. The post-surgical margin of the cavity was infiltrated with lipid-complexed thymidine kinase suicide gene coadministrated with ganciclovir. Toxicity was minimal or absent in all patients. With respect to surgery-treated controls (SC), this combined treatment (CT) significantly increased the fraction of patients local disease-free from 6 to 58% and distant metastases-free from 43 to 78% (Fisher's Exact test). In addition, CT significantly improved both SC overall 78 (23-540) and metastasis-free survival 112 (0-467) days to more than 1312 days (respective ranges: 43-1312 and 0-1312) (Kaplan-Meier analysis). In those patients subjected to partial surgery or presenting local recurrence, the efficacy of CT was verified by a 49% of objective responses that averaged 85% of tumor mass loss, while 22% displayed tumor progression as 94% of SC did. Therefore, surgery adjuvant CT controlled tumor growth, delaying or preventing post-surgical recurrence and distant metastasis, significantly extending survival and recovering the quality of life.
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PMID:Cytokine-enhanced vaccine and suicide gene therapy as surgery adjuvant treatments for spontaneous canine melanoma. 1803 8

Canine spontaneous melanoma is a highly aggressive tumor resistant to current therapies. We evaluated the safety, efficacy and antitumor effects of direct intratumor injections of lipoplexes encoding herpes simplex thymidine kinase coadministrated with ganciclovir, and irradiated transgenic xenogeneic cells secreting 20-30 mug day(-1) of human granulocyte-macrophage colony-stimulating factor and interleukin-2. Toxicity was minimal or absent in all patients. This combined treatment (CT) induced tumor regression and a pronounced immune cell infiltration. The objective responses (47%: 21/45) averaged 80% of tumor mass loss. Local CT also induced systemic antitumor response evidenced by complete remission of one pulmonary metastasis and by the significantly higher percentage of metastasis-free patients (76: 34/45)) until the study ending compared to untreated (UC: 29%, 5/17), surgery-treated (CX: 48%, 11/23) or suicide gene-treated controls (SG: 56%, 9/16) (Fisher's exact test). CT significantly improved median survival time: 160 (57-509) days compared to UC (69 (10-169)), CX (82 (43-216)) or SG (94 (46-159)). CT also increased (P<0.00001, Kaplan-Meier analysis) metastasis-free survival: >509 (57-509) days with respect to UC: 41 (10-169), CX: 133 (43-216) and SG: >159 (41-159). Therefore, CT controlled tumor growth by delaying or preventing distant metastasis, thereby significantly extending survival and recovering the quality of life.
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PMID:Suicide gene and cytokines combined nonviral gene therapy for spontaneous canine melanoma. 1821 42


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