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)

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

Polysaccharides extracted from human tubercle bacilli (specific substance of Maruyama) have been clinically applied in patients with malignant diseases in Japan and other countries. It is known that increased colorectal carcinogenesis occurs in patients with ulcerative colitis. The repeated mucosal necrosis-regeneration sequence in chronic ulcerative colitis induced with 3 % dextran sulfate sodium led to colorectal carcinogenesis in azoxymethane-pretreated mice. Simultaneously multiple injections with the polysaccharides reduced the increases in thymidylate synthase and thymidine kinase activities and a number of bromodeoxyuridine-incorporated S-phase cells in colorectal tissues resulted in the reduction of tumorous regions with high-grade dysplasia.
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PMID:Polysaccharides extracted from human tubercle bacilli (specific substance of Maruyama) reduces carcinogenesis in murine ulcerative colitis. 1120 61

A new class of 5-(1-cyanamido-2-haloethyl)-2'-deoxyuridines (4-6) and arabinouridines (7, 8) were synthesized by the regiospecific addition of halogenocyanamides (X-NHCN) to the 5-vinyl substituent of the respective 5-vinyl-2'-deoxyuridine (2) and 2'-arabinouridine (3). Reaction of 2 with sodium azide, ceric ammonium nitrate, and acetonitrile-methanol or water afforded the 5-(1-hydroxy-2-azidoethyl)-(10) and 5-(1-methoxy-2-azidoethyl)-2'-deoxyuridines (11). In vitro antiviral activities against HSV-1-TK(+) (KOS and E-377), HSV-1-TK(-), HSV-2, VZV, HCMV, and DHBV were determined. Of the newly synthesized compounds, 5-(1-cyanamido-2-iodoethyl)-2'-deoxyuridine (6) exhibited the most potent anti-HSV-1 activity, which was equipotent to acyclovir and superior to 5-ethyl-2'-deoxyuridine (EDU). In addition, it was significantly inhibitory for thymidine kinase deficient strain of HSV-1 (EC(50) = 2.3-15.3 microM). The 5-(1-cyanamido-2-haloethyl)-2'-deoxyuridines (4-6) all were approximately equipotent against HSV-2 and were approximately 1.5- and 15-fold less inhibitory for HSV-2 than EDU and acyclovir, respectively. Compounds 4-6 were all inactive against HCMV but exhibited appreciable antiviral activity against VZV. Their anti-VZV activity was similar or higher to that of EDU and approximately 5-12-fold lower than that of acyclovir. The 5-(1-cyanamido-2-haloethyl)-(7,8) analogues of arabinouridine were moderately inhibitory for VZV and HSV-1 (strain KOS), whereas compounds 10 and 11 were inactive against herpes viruses. Compounds 5 and 6 also demonstrated modest anti-hepatitis B virus activity against DHBV (EC(50) = 19.9-23.6 microM). Interestingly, the related 5-(1-azido-2-bromoethyl)-2'-deoxyuridine (1n) analogue proved to be markedly inhibitory to DHBV replication (EC(50) = 2.6-6.6 microM). All compounds investigated exhibited low host cell toxicity to several stationary and proliferating host cell lines as well as mitogen-stimulated proliferating human T lymphocytes.
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PMID:Synthesis and antiviral activity of novel 5-(1-cyanamido-2-haloethyl) and 5-(1-hydroxy(or methoxy)-2-azidoethyl) analogues of uracil nucleosides. 1158 57

The incidence of colorectal carcinogenesis is increased in patients with ulcerative colitis. We investigated the effects of repetitive diarrhea on colorectal carcinogenesis in mice singly pretreated by a low-dose of chemical carcinogen. Mucosal changes were investigated in mice pretreated with a single intraperitoneal injection of 8.0 mg/kg body weight of azoxymethane prior to a repetitive oral administration of 3% dextran sulphate sodium to induce chronic diarrhea. Repetitive treatment with dextran sulphate sodium induced a cycle of chronic diarrhea-remission in the colorectum. Five submucosal-invasive adenocarcinomas and 65 high-grade dysplasias were found in 15 mice that underwent azoxymethane-pretreatment with 3 cycles of 3% dextran sulphate sodium-exposure, i.e. colorectal carcinogenesis was observed mainly in the left side of the large intestine within 11 weeks after the initial treatment with carcinogen. Consequently, thymidine kinase was expressed and activated, and an increase in bromodeoxyuridine-immuno-reactive (S-phase) cells was observed in the regenerating mucosa and the colorectum with tumorous lesions. Colorectal carcinogenesis developed with the increasing duration of diarrhea induced by 3% dextran sulphate sodium in mice pretreated by a single injection of a small dosage of azoxymethane during the comparatively short period of this experimental colitis system.
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PMID:The more an ulcerative colitis is repeated, the more the risk of colorectal carcinogenesis is increased in mice. 1255 18

The purpose of the present study was to evaluate both in vitro and in vivo a series of boron-containing nucleosides that potentially could be used as delivery agents for neutron capture therapy. The rationale for their synthesis was based on the fact that proliferating neoplastic cells have increased requirements for nucleic acid precursors, and, therefore, they should preferentially localize in the tumor. A series of 3-carboranlyalkyl thymidine analogs has been synthesized and a subset, designated N4, N5, and N7, and the corresponding 3-dihydroxypropyl derivatives, designated N4-2OH, N5-2OH, and N7-2OH, have been selected for evaluation. Using these compounds as substrates for recombinant human thymidine kinase-1 and the mitochondrial isoenzyme thymidine kinase-2, the highest phosphorylation levels relative to thymidine were seen with N5 and the corresponding dihydroxypropyl analog N5-2OH. In contrast, N4, N4-OH, N7, and N7-OH had substantially lower phosphorylation levels. To compare compounds with high and low thymidine kinase-1 substrate activity, N5 and N7 and the corresponding dihydroxypropyl derivatives were selected for evaluation of their cellular toxicity, uptake and retention by the F98 rat glioma, human MRA melanoma, and murine L929 cell lines, all of which are thymidine kinase-1(+), and a mutant L929 cell line that is thymidine kinase-1(-). N5-2OH was the least toxic (IC50, 43-70 microm), and N7 and N7-2OH were the most toxic (IC50, 18-49 microm). The highest boron uptake was seen with N7-2OH by the MRA 27 melanoma and L929 wild-type (wt) cell lines. The highest retention was seen with L929 (wt) cells, and this ranged from 29% for N5-2OH to 46% for N7. Based on the in vitro toxicity and uptake data, N5-2OH was selected for in vivo biodistribution studies either in rats bearing intracerebral implants of the F98 glioma or in mice bearing either s.c. or intracerebral implants of L929 (wt) tumors. At 2.5 hours after convection-enhanced delivery, the boron values for the F98 glioma and normal brain were 16.2 +/- 2.3 and 2.2 microg/g, respectively, and the tumor to brain ratio was 8.5. Boron values at 4 hours after convection-enhanced delivery of N5-2OH to mice bearing intracerebral implants of L929 (wt) or L929 thymidine kinase-1(-) tumors were 39.8 +/- 10.8 and 12.4 +/- 1.6 microg/g, respectively, and the corresponding normal brain values were 4.4 and 1.6 microg/g, thereby indicating that there was selective retention by the thymidine kinase-1(+) tumors. Based on these favorable in vitro and in vivo data, neutron capture therapy studies will be initiated using N5-2OH in combination with two non-cell cycle dependent boron delivery agents, boronophenylalanine and sodium borocaptate.
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PMID:Boron-containing nucleosides as potential delivery agents for neutron capture therapy of brain tumors. 1534 17

A simple and rapid capillary electrophoretic method was developed for the simultaneous determination of thymidylate (TMP) and thymidine 5'-diphosphate (TDP) in enzyme assays without using radioactive-labeled substrates. Prior to electrophoretic separation, addition of acetonitrile and sodium chloride to the assay solution and brief centrifugation are recommended for the purpose of sample cleanup and sample stacking. The separation of micromolar TMP and TDP from millimolar adenosine 5'-triphosphate (ATP) was performed at 25 degrees C using sodium tetraborate as the background electrolyte. Under the optimal condition, a good separation with high efficiency was achieved in 6 min. Several parameters affecting the separation were studied, including the pH of electrolyte, the applied voltage, and acetonitrile-salt sample stacking. The fronting of the ATP peak resulting from the interference of magnesium ion in the enzyme assay buffer was suppressed by the addition of sodium ethylenediaminetetraacetate to the sample solution. Using deoxyadenylate as an internal standard, the linear range of the method was 5-200 microM, and the concentration limits of detection of TMP and TDP were 2.6 and 3.8 microM, respectively. Application of the proposed method for simultaneous determination of TMP and TDP in enzyme assays was demonstrated by the activity assays of thymidine kinase and thymidylate kinase from white spot syndrome virus. This is a sensitive, nonradioactive method for thymidine kinase and thymidylate kinase assays.
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PMID:Simultaneous determination of thymidylate and thymidine diphosphate by capillary electrophoresis as a rapid monitoring tool for thymidine kinase and thymidylate kinase activities. 1588 May 57

SCN5A encodes the predominant voltage-gated sodium channel isoform in human heart and nearly 100 variants have now been described and studied in vitro. However, development of animal models to analyze function of such large numbers of human gene variants represents a continuing challenge in translational medicine. Here, we describe the implementation of a two stage procedure, recombinase-mediated cassette exchange (RMCE), to efficiently and rapidly generate mice in which a full-length human cDNA replaces expression of the murine ortholog. In the first step of RMCE, conventional homologous recombination in mouse ES cells was used to replace scn5a exon 2 (that contains the translation start site) with a cassette acceptor that includes the thymidine kinase gene, flanked by loxP/inverted loxP sites. In the second step, the cassette acceptor site was replaced by the full-length wild-type human SCN5A cDNA by Cre/loxP-mediated recombination. The exchange event occurred in 7/29 (24%) colonies, and the time from electroporation to first homozygotes was only 8 months. PCR-restriction fragment length polymorphism (RFLP) showed that the murine isoform was replaced by the human one, and functional studies indicated that mice with human cardiac sodium channels have wild-type sodium current density, action potential durations, heart rates, and QRS durations. These data demonstrate that RMCE can be used to generate mice in which a targeted allele can be rapidly and efficiently replaced by variants of choice, and thereby can serve as an enabling approach for the functional characterization of ion channel and other DNA variants.
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PMID:Recombinase-mediated cassette exchange to rapidly and efficiently generate mice with human cardiac sodium channels. 1708 9

An increased incidence of colorectal carcinoma is known to occur in patients with ulcerative colitis (UC), which displays a cycle of recurrence-remission in the colorectal mucosa. Fluvastatin, an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, is a hypocholesterolemic agent effective in animals and humans. Repeated administration of 3% dextran sulfate sodium subsequent to a single intraperitoneal injection of azoxymethane induces chronic UC resulting in an increased incidence of high-grade dysplasia and submucosal-invasive adenocarcinomas in the mouse colorectum. The effects of fluvastatin as an antioxidant on colorectal carcinogenesis in mice with UC were investigated. Treatment with fluvastatin in mice with UC abolished the anemia caused by colorectal carcinogenesis, and markedly lowered plasma lipid levels resulting in a reduction of colitis and carcinogenesis, shown by inhibition of the decrease in colorectal length, the increased number of foci of gland loss with inflammatory cell infiltration indicating the severity of UC and incidence of colorectal dysplasia, respectively, with a reduction in anti-8-hydroxy-2'-deoxyguanosine (8-OHdG) antibody (a biological marker of in vivo oxidative DNA damage)-positive cells of the colorectal mucosa and the activity of the DNA-synthesizing enzyme thymidine kinase in colorectal tissues.
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PMID:Preventive effect of fluvastatin on ulcerative colitis-associated carcinogenesis in mice. 1720 Nov 37

Arsenic compounds are generally considered as poor inducers of gene mutations. To investigate the mutagenicity of several arsenic compounds at the thymidine kinase (Tk) gene, a reporter gene for mutation induction, we used the mouse lymphoma assay (MLA). This test is widely applied and detects a broad spectrum of mutational events, from point mutations to chromosome alterations. The selected arsenic compounds were two inorganic (sodium arsenite and arsenic trioxide) and four organic compounds (monomethylarsonic acid, dimethylarsinic acid, tetraphenylarsenium and arsenobetaine). The results show that sodium arsenite, arsenic trioxide, monomethylarsonic acid and dimethylarsinic acid are mutagenic, showing a clear dose-response pattern. On the other hand, tetraphenylarsenium and arsenobetaine are not mutagenic. Inorganic arsenic compounds are the more potent agents producing significant effects in the micromolar range, while the mutagenic organic arsenic compounds induce similar effects but in the millimolar range.
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PMID:Gene-mutation induction by arsenic compounds in the mouse lymphoma assay. 1785 Nov 18

An increased incidence of colorectal carcinoma is known to occur in patients with ulcerative colitis (UC), which displays a cycle of recurrence-remission in the colorectal mucosa. Repeated oral doses of 3% dextran sulfate sodium subsequent to a single intraperitoneal injection of azoxymethane induced a chronic UC resulting in an increased incidence of high-grade dysplasia and submucosal-invasive adenocarcinomas in the mouse colorectum. The active form of vitamin D(3) is a calcium-regulating hormone that increases serum calcium levels and intestinal calcium absorption. It has been reported that there is an inverse correlation between serum levels of the active metabolite of vitamin D and colorectal carcinoma stage. The features of the colitis induced in this animal model are very similar to the UC in patients in terms of both clinical and histological characteristics. Treatment with a vitamin D(3) analog, alfacalcidol, in mice prevented colitis and carcinogenesis; this is shown by inhibition of the decrease in colorectal length and inhibition of the increased incidence of colorectal dysplasia, with a reduction in the mRNA expression of the DNA-synthesizing enzyme, thymidine kinase, in colorectal tissues.
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PMID:Chemopreventive effect of a vitamin D(3) analog, alfacalcidol, on colorectal carcinogenesis in mice with ulcerative colitis. 1789 19


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