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

Human cells salvage pyrimidine deoxyribonucleosides via 5'-phosphorylation which is also the route of activation of many chemotherapeutically used nucleoside analogs. Key enzymes in this metabolism are the cytosolic thymidine kinase (TK1), the mitochondrial thymidine kinase (TK2) and the cytosolic deoxycytidine kinase (dCK). These enzymes are expressed differently in different tissues and cell cycle phases, and they display overlapping substrate specificities. Thymidine is phosphorylated by both thymidine kinases, and deoxycytidine is phosphorylated by both dCK and TK2. The enzymes also phosphorylate nucleoside analogs with very different efficiencies. Here we present specific radiochemical assays for the three kinase activities utilizing analogs as substrates that are by more than 90 percent phosphorylated solely by one of the kinases; i.e. 3'-azido-2',3'-dideoxythymidine (AZT) as substrate for TK1, 1-beta-D-arabinofuranosylthymidine (AraT) for TK2 and 2-chlorodeoxyadenosine (CdA) for dCK. We determined the fraction of the total deoxycytidine and thymidine phosphorylating activity that was provided by each of the three enzymes in different human cells and tissues, such as resting and proliferating lymphocytes, lymphocytic cells of leukemia patients (chronic lymphocytic, chronic myeloic and hairy cell leukemia), muscle, brain and gastrointestinal tissue. The detailed knowledge of the pyrimidine deoxyribonucleoside kinase activities and substrate specificities are of importance for studies on chemotherapeutically active nucleoside analogs, and the assays and data presented here should be valuable tools in that research.
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PMID:Selective assays for thymidine kinase 1 and 2 and deoxycytidine kinase and their activities in extracts from human cells and tissues. 135 86

The effect of alpha-interferon (alpha-IFN) on spontaneous or induced proliferation of isolated peripheral blood mononuclear cells from 5 hairy cell leukemia patients was studied. alpha-IFN inhibited the low spontaneous proliferation of B-ly7 positive hairy cells (HCs) and also the proliferation induced by tumour necrosis factor (TNF). Interleukin-2 did not affect HCs, but induced CD4 positive T cells to proliferate, an effect which alpha-IFN antagonized. The stimulatory effect of TNF on the growth of HCs proved to be reversible and was partially blocked with either anti-TNF receptor or anti-lymphotoxin antibodies. Cellular or secreted thymidine kinase levels reflected the proliferative state of HCs in response to different in vitro treatments, as confirmed by thymidine incorporation and cell cycle studies.
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PMID:alpha-Interferon inhibits spontaneous and induced DNA synthesis in hairy cell leukemia. 147 34

Deoxynucleoside kinases are key enzymes in deoxyribonucleoside salvage, activating several clinically important chemotherapeutic drugs. The four known kinases, cytosolic thymidine kinase (TK1) and deoxycytidine kinase (dCK) and the mitochondrial thymidine kinase (TK2) and deoxyguanosine kinase (dGK), have been purified and characterized as to the subunit structure as well as specificity with a large number of analogs. These results are summarized and used to establish selective assays for the four enzymes in crude extracts of normal and malignant human peripheral blood mononuclear cells, gastrointestinal tissues and sarcomas. TK2 and dGK activities were found at low levels in all tissues, possibly correlated to the content of mitochondria. TK1 activity was detected only in samples containing a significant number of S phase cells. We have measured dCK activity as well as dCK polypeptide level by immuno blotting in these extracts. High levels of dCK were found in normal mononuclear leukocytes (91-145 ng dCK/mg protein) and in B-cell chronic lymphocytic leukemia (80 +/- 30 ng/mg, n = 23). Hairy cell leukemia contained lower levels (28 +/- 23 ng/mg, n = 7), as did unexpectedly three samples of T-cell chronic lymphocytic leukemia (18 +/- 14 ng/mg). Phytohemaglutinine stimulation of normal lymphocytes did not lead to any substantial increase in either dCK activity or expression (less than 2.5-fold). In colon adenocarcinomas, the dCK content was significantly higher (21 +/- 9.3 ng/mg, n = 20) than in normal colon mucosa (8.2 +/- 3.7 ng/mg, n = 19, p < 0.05). A similar pattern of dCK expression was found in gastric adenocarcinomas (21 +/- 13 ng/mg, n = 5) and normal ventricular mucosa (6.2 +/- 5.4 ng/mg, n = 5, p < 0.15). One leiomyosarcoma and one extra-skeletal osteosarcoma showed a dCK levels comparable to those found in normal lymphocytes (84 +/- 6 and 109 +/- 4 ng/mg), while other sarcoma samples contained levels comparable to the gastrointestinal adenocarcinomas (20 +/- 7 ng/mg, n = 12). We confirm that dCK is expressed constitutively and predominantly in lymphoid cells, but conclude that a significant expression may be found in non-lymphoid tissues as well, with increased levels in the corresponding tumor tissue. 2-Chlorodeoxyadenosine (CdA), an antileukemic agent used in treatment of hairy cell leukemia and chronic lymphocytic leukemias (B-CLL), is phosphorylated by dCK which was used as the selective substrate for this enzyme. A study was performed to investigate if there was a correlation between the dCK levels and the response to CdA treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Properties and levels of deoxynucleoside kinases in normal and tumor cells; implications for chemotherapy. 794 71

The serum levels of soluble ICAM-1 (CD54) were significantly elevated in patients with non-Hodgkin's lymphomas (NHL, n=127) and hairy cell leukaemia (HCL, n=15) compared with healthy controls (n=31). In high-grade malignant NHL (n=79) the sICAM-1 levels correlated with the tumour mass as reflected in the Ann Arbor staging system but not with bulky disease. Further, the sICAM-1 levels correlated with disease activity as reflected by the presence of B symptoms and with other known prognostic markers. In particular serum thymidine kinase (sTK). In patients with low-grade malignant NHL (n=48) a trend towards higher serum levels of sICAM-1 was found in patients with advanced stage and B symptoms. In both low and high-grade malignant NHL, elevated levels of sICAM-1 were associated with poorer overall and disease-free survival. The present results indicated that sICAM-1 levels have a prognostic power equal to that of other serum markers claimed to be of prognostic value in NHL, namely serum lactate dehydrogenase (LDH), erythrocyte sedimentation rate (ESR), beta-2-microglobulin (beta2m), serum thymidine kinase (sTK), albumin and orosomucoid. The cellular origin and the possible interactions between soluble and surface ICAM-1 and its ligands needs further exploration.
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PMID:Elevated serum levels of soluble ICAM-1 in non-Hodgkin's lymphomas correlate with tumour burden, disease activity and other prognostic markers. 879 Jan 63

A replication defective herpes simplex virus-1 was evaluated as a therapeutic vector. Mantle cell lymphoma (MCL), hairy cell leukemia (HCL), and B-cell chronic lymphocytic leukemia (B-CLL) were chosen because leukemic cells were collectable from peripheral bloods in these diseases. Cells from six MCL, one HCL, and nine B-CLL were infected in vitro with T0Z.1 at 3 multiplicity of infection (MOI). Herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV)-mediated suicide gene therapy showed 14.7% of mean tumor killing against leukemic B-cell malignancies. The mean tumor-killing effects were 8.7 and 17.1% in MCL and B-CLL, respectively. The effect against HCL was 29%. The study indicates that herpes simplex virus (HSV)-based gene therapy might be an effective strategy.
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PMID:In vitro thymidine kinase/ganciclovir-based suicide gene therapy using replication defective herpes simplex virus-1 against leukemic B-cell malignancies (MCL, HCL, B-CLL). 1280 27

Hairy cell leukemia (HCL), a B cell malignancy comprising 2 % of all leukemias, has become quite exciting recently with regard to the development of new targets for therapy. This review will focus on advancements made within the past 1-2 years in targeted therapy for this disease. These advances may be grouped into two very difference categories, namely targeting of CD22 with the recombinant immunotoxin moxetumomab pasudotox, and targeting of the mutated BRAF component of the MAP kinase pathway. Moxetumomab pasudotox in phase I testing was recently reported to be associated with an overall response rate of 86 % and a complete remission (CR) rate of 46 % in 28 patients with relapsed and refractory HCL. Many of the CRs are without minimal residual disease (MRD). Severe or dose limiting toxicity was not observed on this trial, but a completely reversible and largely asymptomatic form of grade 2 hemolytic uremic syndrome occurred in two patients during retreatment. This agent has commenced phase III multicenter testing to validate its phase I results. An extensive number of studies have documented the V600E mutation in nearly all HCL patients, but not in similar hematologic malignancies. The thymidine kinase inhibitor vemurafenib, which inhibits the V600E mutant of BRAF, was reported to induce a CR in multiply relapsed and refractory HCL, with nearly complete clearing of MRD. One additional partial and one additional complete remission were subsequently reported.
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PMID:Hairy cell leukemia-new genes, new targets. 2389 6