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)

The current study was undertaken to determine the relevance of leukemic blast cell proliferative activity, cellular parameters of Ara-C metabolism and the in vitro sensitivity to GM-CSF in association with the clinical response to TAD-9 induction therapy in 66 patients with de novo acute myeloid leukemia (AML). Proliferative activity was assessed by 3H-thymidine (3H-TdR) incorporation and thymidine kinase (TK) activity, parameters of Ara-C metabolism comprised the activities of deoxycytidine kinase (DCK) and DNA polymerase alpha (poly alpha) as well as Ara-CTP concentrations and 3H-Ara-C uptake into DNA. GM-CSF sensitivity was determined by in vitro incubation of blasts for 48 h with or without GM-CSF (100 U/ml) followed by an additional 4 h concurrent exposure to GM-CSF and 3H-TdR (0.5 microCi/ml). The following results were obtained as expressed by median values and ranges: 3H-TdR incorporation: 1.07 pmol/10(5) cells (0.0-10.1), TK: 7.3 pmol/min/mg protein (1.3-56.0), DCK: 9.3 pmol/min/mg protein (0.77-47.1), poly alpha: 1.7 pmol/min/mg protein (0.00-28.9), Ara-CTP: 53.3 ng/10(7) cells (13.3-211.0), 3H-Ara-C uptake: 0.06 pmol/10(5) cells (0.0-0.57). 3H-Ara-C uptake was correlated with 3H-TdR incorporation (r = 0.74) and with the (S-phase dependent) activities of TK (r = 0.73) and poly alpha (r = 0.71, but not with DCK activity or intracellular Ara-CTP content. Blast cells of 37 from 55 analyzed patients were found to be sensitive to GM-CSF stimulation as defined by an increase in 3H-TdR incorporation > or = 1.5-fold over control values after the 48 h GM-CSF exposure. In vitro data were related with clinical response to TAD-9 induction therapy in 43 patients with newly diagnosed AML, taking the blast cell reduction at day 10 or 16 to < 5% or > or = 5% residual blasts as early parameter for adequate or inadequate response, respectively. While neither 3H-Ara-C uptake, nor intracellular Ara-CTP concentration, TK nor DCK activity were predictive for response, a high 3H-TdR incorporation and a high poly alpha activity were associated with adequate blast cell reduction. Median values of 3H-TdR incorporation were 2.26 pmol/10(5) cells for patients with adequate blast cell clearance and 0.80 pmol/10(5) cells for patients with inadequate blast cell clearance (P = 0.11), the respective values for poly alpha were 3.22 pmol/min/mg protein for responders and 1.1 pmol/min/mg protein for non-responders (P = 0.0085).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Blast cell proliferative activity and sensitivity to GM-CSF in vitro are associated with early response to TAD-9 induction therapy in acute myeloid leukemia. 747 75

Granulocyte-macrophage (GM)-CSF and IL-3 are hemopoietic growth factors whose genes are closely linked in both humans and mice. In humans, the GM-CSF and IL-3 genes are regulated by a cyclosporin A-inhibitable enhancer located 3 kb upstream of the GM-CSF gene that is inducible by signals that mimic TCR activation. To search for a murine homologue of this enhancer we probed mouse genomic DNA and located a 400-bp element 2 kb upstream of the mouse GM-CSF gene that was 76% homologous with the human GM-CSF enhancer. Like the human GM-CSF enhancer, this element formed a cyclosporin A-inhibitable DNase I-hypersensitive site in the murine T cell line EL4 upon activation with phorbol ester and calcium ionophore. Transient transfection assays showed that this homologue of the human enhancer acted as an inducible enhancer of the thymidine kinase promoter, the mouse IL-3 promoter, and the human GM-CSF promoter. We observed, however, that the mouse GM-CSF promoter was significantly more active than the human GM-CSF promoter and found that it supported a level of activity equivalent to the combination of the human GM-CSF promoter and the human GM-CSF enhancer. Consequently, the activity of mouse GM-CSF promoter was not significantly elevated in the presence of the mouse GM-CSF enhancer. Because the mouse GM-CSF enhancer is considerably less active than its human homologue we suggest that the mouse GM-CSF gene has evolved with less dependence upon the upstream enhancer for its activation.
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PMID:Transcriptional regulation of mouse granulocyte-macrophage colony-stimulating factor/IL-3 locus. 760 99

We previously demonstrated stable integration of a transduced thymidine kinase (TK)-neo gene into immature and replatable stem and progenitor cells, as assessed by the presence of the gene in second-generation colonies. To evaluate whether this integration was still present in third- and fourth-generation colonies, nonadherent low-density T-lymphocyte-depleted (NALT-) cells from human umbilical cord blood were prestimulated with recombinant human (rhu) erythropoietin (Epo), steel factor (SLF), interleukin-3 (IL-3), granulocyte-macrophage (GM) colony-stimulating factor (CSF), and granulocyte (G)-CSF. Prestimulated NALT- cells were incubated with retroviral-containing supernatant obtained from TK-neo vector-producing cells, washed, and assayed for colony formation in the presence of Epo, SLF, IL-3, GM-CSF, and G-CSF -/+ G418. The results confirmed that the TK-neo gene could be efficiently introduced into hematopoietic progenitor cells without stromal cells as a source of virus. As previously reported, proviral integration was detected in primary G418R-colonies, and in second-generation replated colonies derived from G418R granulocyte erythroid macrophage megakaryocyte colony-forming units and high-proliferative potential colony-forming cells (HPP-CFCs). Moreover, we now document that proviral integration was apparent in cells from colonies derived from third- and fourth-generation replated HPP-CFC, suggesting a high degree of stable integration of the transduced gene.
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PMID:Stable integration of retrovirally transduced genes into human umbilical cord blood high-proliferative potential colony-forming cells (HPP-CFC) as assessed after multiple HPP-CFC colony replatings in vitro. 774 19

Lung cancer is a leading cause of cancer death and standard chemotherapies are resulting in only marginal improvements in outcome. Experimental approaches involving gene therapy are attractive in this clinical setting. There are two basic types of genes utilized, either those intended to induce immunity or those that are directly tumoricidal. Immunity-inducing genes that have been used in model (and some human) systems include MHC molecules, costimulatory molecules, and cytokines such as IL-2, IL-4, IL-6, GM-CSF. These are intended to induce effective systemic immune responses against tumor antigens which would not otherwise develop. Direct toxic approaches include the reintroduction of tumor suppressor genes or enzymes which convert non-toxic drugs to toxic ones, such as herpes thymidine kinase. As a means for gene delivery, retroviruses are the most common vehicle, although Adenovirus vectors and direct DNA delivery have specific advantages.
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PMID:Gene therapy for lung cancer. 861 19

The effectiveness of combination therapy using a suicide gene and cytokine genes for the treatment of metastatic colon carcinoma in the mouse liver was investigated. Pre-established hepatic tumors treated with a recombinant adenoviral vector containing the herpes simplex virus thymidine kinase gene(tk) exhibited substantial regression, although all treated animals suffered from subsequent relapses. Although cotreatment with a mouse interleukin 2 (mIL-2)-containing adenoviral vector induced an effective antitumor immune response, the immunity waned with time, and the treated animals eventually succumbed to hepatic tumor relapse or distant metastases. In this study, mouse granulocyte macrophage colony-stimulating factor (mGM-CSF) gene was tested for its ability to further enhance and prolong the antitumoral cellular immunity. A fraction of the animals treated with tk + mIL-2 + mGM-CSF developed long-term antitumor immunity and survived for more than 4 months without recurrence. This long-term antitumor immunity could be enhanced further by subsequent "vaccination" with mIL-2-expressing parental tumor cells. The results indicate that local expression of GM-CSF in the hepatic tumors and prolonged mIL-2 expression are necessary to generate persistent antitumor immunity that is essential for the prevention of tumor recurrence and long-term animal survival.
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PMID:Combination suicide and cytokine gene therapy for hepatic metastases of colon carcinoma: sustained antitumor immunity prolongs animal survival. 870 21

The strategies of gene therapy for cancer can be classified as: 1. regulation of oncogenes and anti-oncogenes, 2. immunogenetherapy, 3. support of chemotherapy, 4. suicide gene therapy, and 5. gene marking. The first one is the strategy to inhibit the expression of oncogenes by their antisenses or rhybozymes, or to introduce anti-oncogenes into those tumor cells with the inactivate effector cells (lymphocytes) by transducing cytokine genes, etc., followed by retransfering the gene-modified effector cells to patients (adoptive immunotherapy). The other one is to augment antigenicity of tumor cells. The immunogenetherapy method has been widely used for 70% of gene therapy of human cancer, because cells can be transduced ex vivo. The anti-tumor effects of human gene therapy using a GM-CSF gene by Muligan et al. or an IL-2 gene by Tahara and Lotze are expected. The third is the strategy to protect bone marrows from large dose of anti-cancer drug by transducing a multidrug resistance gene into those bone marrow cells or periphen blood stem cells, overcoming dose limiting of the drug. The fourth strategy is to transduce the herpes simplex virus thymidine kinase (KSV-TK) gene for activating the cytocydal prodrug (ganciclovir: GCV) into tumor cells in order to kill the tumor cells themselves following administration of GCV. At present, vectors most widely used for gene transduction are retroviruses and adenoviruses. However, the transduction using these vectors are primarily conducted ex vivo. The direct in vivo gene delivery method to target tumor cells are required.
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PMID:[Gene therapy for cancer]. 872 70

We made several generic plasmids for construction of recombinant vaccinia virus (rvv) expressing foreign proteins in high yield. Rvvs expressing biologically active Escherichia coli beta-galactosidase (rvv-lacZ) and the cytokine murine GM-CSF (rvv-mGM-CSF) were constructed by using these plasmids. To obtain attenuated rvv, cDNA for these proteins was inserted in the thymidine kinase gene of vaccinia virus. Their expression was controlled by vaccinia early/late promoter, 7.5 K so that these proteins could be expressed in the infected cells throughout the life cycle of the virus. Female C57BL/6 mice were immunized subcutaneously with B16-F10 melanoma cells infected with rvv, and 2 weeks later challenged with viable B16 cells. Mice immunized with rvv-mGM-CSF showed delay in tumor development, smaller tumor volumes and longer survival time compared with unimmunized mice, as well as mice immunized with rvv-lacZ. Mice immunized with rvv-mGM-CSF followed by a booster injection after 1 week responded slightly better than those immunized once, but this difference was not statistically significant. These results suggested that rvv-mGM-CSF could be a promising vaccine for cancer therapy.
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PMID:Construction of recombinant vaccinia virus expressing GM-CSF and its use as tumor vaccine. 892 12

A recombinant vaccinia virus containing and expressing the gene for murine granulocyte-macrophage colony-stimulating factor (VVGM-CSF) was constructed and tested for its antitumor activity. A murine tumor model was established by injecting 10(5) B16F10 melanoma cells into the right rear leg of C57BL/6 mice. Three days after B16F10 inoculation, VVGM-CSF or a thymidine kinase gene-deficient vaccinia virus (VVTK) were injected intratumorly twice weekly for 3 weeks. The results showed that VVGM-CSF treatment significantly inhibited the growth of subcutaneous tumor and delayed the survival period of tumor-bearing mice. Splenic lymphokine-activated killer cell, natural killer cell, and cytotoxic T lymphocyte activities were not found to be altered after VVGM-CSF or VVTK therapy. Cytotoxic and phagocytic activity of peritoneal macrophages were found to be greatly elevated in mice treated with VVGM-CSF. Nitric oxide released from the macrophages was also increased. Considering these data, we may speculate that continuous secretion of GM-CSF and activation of macrophages may contribute to the antitumor effects of VVGM-CSF injected intratumorally.
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PMID:Intratumoral injection of GM-CSF gene encoded recombinant vaccinia virus elicits potent antitumor response in a mixture melanoma model. 908 Jan 23

A recombinant vaccinia virus containing and expressing the gene of murine granulocyte-macrophage colony-stimulating factor (VVGM-CSF) was tested for its antitumor activity. Murine pulmonary metastasis was established by injecting 2 x 10(5) B16F10 melanoma cells into tail vein of C57BL/6 mouse. Three days after B16F10 inoculation, VVGM-CSF or VVTK, a thymidine kinase gene deficient vaccinia virus, was injected intraperitoneally twice weekly for 2 weeks. Two weeks later mice were sacrificed and pulmonary metastasis foci counted. The results showed that VVGM-CSF treatment significantly decreased the number of pulmonary metastasis and prolonged the survival time of tumor-bearing mice (P < 0.01). Cytotoxic and phagocytic activities of peritoneal macrophages were found to be markedly elevated in mice treated with VVGM-CSF. Nitric oxide released from macrophages was also found to be increased. Based on these data, together with our previous results, we may speculate that continuous secretion of GM-CSF and activation of macrophages might partially explain the antitumor effects of VVGM-CSF.
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PMID:[Therapeutic effect of vaccinia virus secreting granulocyte-macrophage colony-stimulating factor on pulmonary metastatic melanoma]. 938 45

In a cancer gene therapy model recombinant adenoviruses expressing the herpes simplex virus thymidine kinase (HSVtk) gene were injected into tumors in situ, either alone or in combination with adenoviruses (Avs) engineered to express IL-2, IL-6 or the costimulatory molecule B7-1. HSVtk phosphorylates the prodrug ganciclovir, thus converting it into an antimetabolite which kills not only HSVtk expressing cells, but also by the 'bystander effect', neighboring untransduced tumor cells. The tumors regressed in 80% of mice upon AvTK/ganciclovir treatment: combinations with AvIL-2, AvIL-6, or AvB7-1 did not improve these results. Cured mice were protected from further challenge with wild-type tumor but not from challenges with an unrelated syngeneic tumor cell line. Since cytotoxic T lymphocyte responses in this tumor model were weak, we analyzed cytokine secretion from spleen cells of treated animals. The best correlate of antitumor immunity in this model was enhanced secretion of GM-CSF, while secretion of IL-2, IL-6 and IFN gamma was also frequently increased but not as consistently. The enhanced IFN gamma secretion associated with unchanged IL-4 secretion suggests that AvTK treatment results in a predominantly Th1-mediated antitumor immune response.
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PMID:Characterization of the antitumor immune response generated by treatment of murine tumors with recombinant adenoviruses expressing HSVtk, IL-2, IL-6 or B7-1. 947 56


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