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

---

Query: EC:2.7.1.21 (thymidine kinase)
7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure of HL-60 cells to 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in specific alterations in thymidine (TdR) metabolism. Within 12 h after treatment with 1.62 nM TPA, the reciprocal alteration in the activities of opposing pathways of TdR metabolism observed during normal culture cell growth was reversed. In TPA-treated cells, the activities of anabolic enzymes, TdR kinase (TK; EC 2.7.1.21) and thymidylate synthase (TS; EC 2.1.1.45), declined to 15% and 18% of those of untreated cells by 96 h. Incorporation of 3H-TdR and 3H-deoxyuridine also decreased in parallel with decline in enzyme activities. In contrast, the activities of catabolic enzymes, TdR phosphorylase (TP; EC 2.4.2.4) and dihydrothymine dehydrogenase (DHT DH; EC 1.3.1.2), increased to 399% and 318% by 96 h. Immunotitration of DHT DH with monoclonal antibody showed that the rise in activity in the differentiated cells was due to the increase in protein amount. Kinetic properties of the enzymes were not altered during differentiation. These metabolic alterations were accompanied by an accumulation of the cells in G1 at the expense of S-phase. Present data indicate that induced differentiation of HL-60 cells results in a reversal of enzymic phenotype of TdR metabolism due to a consequence of decreased proliferation and suggest that emergence of TdR metabolic imbalance may serve as early markers of differentiation of these cells.
...
PMID:Reversal of enzymic phenotype of thymidine metabolism in induced differentiation of HL-60 cells. 261 69

Exposure of U-937 cells to 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in specific alterations in thymidine metabolism. Within 24 h after treatment with 1.62 x 10(-9) M TPA, the reciprocal alteration in the activities of opposing enzymes of thymidine metabolism observed during normal cell culture growth was reversed. In TPA-treated cells, the activities of anabolic enzymes thymidine kinase (EC 2.7.1.75)and thymidylate synthase (EC 2.1.1.45) declined with time linearly to 20 and 16% of those of untreated cells by 72 h. Incorporation of [3H]thymidine and [3H]deoxyuridine into acid-insoluble fractions also decreased in parallel with the decline in enzyme activities. In contrast, the activities of catabolic enzymes thymidine phosphorylase (EC 2.4.2.4) and dihydrothymine dehydrogenase (EC 1.3.1.2) increased. The rise in thymidine phosphorylase activity peaked at 48 h with 406% elevation over the control. The activity of dihydrothymine dehydrogenase was not altered for the first 24 h, but it increased up to 338% by 96 h. Immunotitration of dihydrothymine dehydrogenase with monoclonal antibody against this enzyme showed that the rise in activity in the differentiated cells was due to the increase in the amount of enzyme protein. No significant difference was observed in the Km values for the substrate of each enzyme between untreated and TPA-treated cells. These metabolic alterations during induced differentiation were in line with the changes in cell morphology and accompanied by an accumulation of the cells in G1 at the expense of S phase. These observations indicate that induced differentiation of U-937 cells results in a reversal of the enzymic phenotype of thymidine metabolism and suggest that emergence of thymidine metabolic imbalance may serve as an early marker of differentiation of these cells.
...
PMID:Reversal of enzymic phenotype of thymidine metabolism in induced differentiation of U-937 cells. 268 98

Benzylacyclouridines were developed as specific and potent competitive inhibitors of uridine phosphorylase with Ki values in the nanomolar range. These compounds have no activity against thymidine phosphorylase, uridine kinase, thymidine kinase and orotate phosphoribosyltransferase. Benzylacyclouridines potentiate the chemotherapeutic effect of FdUrd. Coadministration of uridine phosphorylase inhibitor with FdUrd caused selective toxicity against tumors with low or no thymidine phosphorylase, but not against the host tissues which have thymidine phosphorylase, and thus retain the capacity to cleave FdUrd, and hence overcome its toxicity. There are distinct differences between uridine phosphorylase and thymidine phosphorylase. Benzylacyclouridines competitively inhibit the nucleoside transport of mammalian cells. The structure-activity relationship of inhibitors of uridine phosphorylase showed that a large hydrophobic pocket exists where C-5 of uracil binds, and that it is necessary to have the 3'-hydroxyl group and syn-configuration around the N-glycosidic bond for the nucleosides or their analogs to bind. Dihydrouracil dehydrogenase was found to be widely distributed among mammalian cells, where it was previously believed to be present only in the liver and the kidney. The structure-activity relationship of its inhibitors revealed benzyloxybenzyluracil and 2,6-pyridinediol as most potent. Also identified for orotate phosphoribosyltransferase was 2,4-pyridinediol.
...
PMID:Development of inhibitors of pyrimidine metabolism. 269 11

The behavior of the activities of thymidine metabolizing enzymes, dihydrothymine dehydrogenase (EC 1.3.1.2) and thymidine phosphorylase (EC 2.4.2.4) for thymidine degradation, thymidine kinase (EC 2.7.1.75) and thymidylate synthase (EC 2.1.1.45) for DNA synthesis, was elucidated in cytosolic extracts from normal human lymphocytes and 13 human leukemia-lymphoma cell lines. In the normal human lymphocytes, the activities of dihydrothymine dehydrogenase, thymidine phosphorylase, thymidine kinase, and thymidylate synthase were 6.88, 796, 0.30, and 0.29 nmol/h/mg protein, respectively. In leukemia-lymphoma cell lines, the activities of synthetic enzymes, thymidine kinase, and thymidylate synthase, increased two- to 79-fold and 22- to 407-fold of the normal lymphocyte values. In contrast, the activities of the catabolic enzymes, dihydrothymine dehydrogenase and thymidine phosphorylase, decreased to 5-42% and 3-38% of the values of normal lymphocytes. As a result, the ratio of activities of thymidine kinase/dihydrothymine dehydrogenase was elevated by 7- to 1170-fold, respectively. Thus, reciprocal behavior in the activities of the opposing enzymes in thymidine metabolism was observed in human leukemia-lymphoma cells. Polyclonal and monoclonal antibodies against dihydrothymine dehydrogenase were prepared and studies on immunotitration of this enzyme with these antibodies showed that the enzyme protein amount in Jurkat leukemic cells was 36% of that of normal lymphocytes. This was in good agreement with the decrease in the activity of the enzyme to 32%, indicating that the decrease in activity in the leukemic cells was due to the decline in the amount of enzyme protein. The metabolic imbalances in thymidine utilization appear to be characteristic of human leukemia-lymphoma cells. These observations should confer selective advantages to the lymphoproliferating cells and mark out the catabolic, as well as the synthetic, enzymes as important targets in the design of chemotherapy.
...
PMID:Behavior of activities of thymidine metabolizing enzymes in human leukemia-lymphoma cells. 291 46

Bromovinyldeoxyuridine (BVDU) is a highly potent and selective antiherpetic agent which offers great potential for the treatment of severe herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) infections in cancer patients. BVDU inhibits the replication of HSV-1 and VZV at a concentration as low as 1-10 ng/ml; and the proliferation of tumor cells transformed with the HSV-1 thymidine kinase gene is even inhibited by BVDU concentrations lower than 1 ng/ml. Moreover, BVDU is inhibitory to Epstein-Barr virus replication in vitro at a concentration of 0.02 micrograms/ml. Due to the action of pyrimidine nucleoside phosphorylases, BVDU is rapidly degraded to the free pyrimidine base bromovinyluracil (BVU). In contrast to BVDU, which is cleared from the bloodstream within 2-3 hours, BVU persists in the plasma for at least 24 hours. During this period BVU can be converted again to BVDU upon administration of deoxythymidine, deoxyuridine or any other deoxyribonucleoside capable of transferring its deoxyribosyl moiety onto BVU. BVU owes its long persistence in the bloodstream to the fact that it does not act as substrate for dihydrothymine dehydrogenase, the enzyme that catalyzes the first step in the catabolic pathway of pyrimidines. On the contrary, BVU acts as an efficient inhibitor of this enzyme and thereby prevents the degradation of fluorouracil (FU), a well-known anticancer agent. As a consequence, BVDU via BVU enhances the antitumor activity of FU, as has been demonstrated in the murine P388 leukemia model. Thus, BVDU may be useful in anticancer chemotherapy from several viewpoints, e.g. for treatment of intercurrent herpesvirus infections, and, in combination with FU, for treatment of those malignant diseases that are amenable to FU therapy.
...
PMID:Potential of bromovinyldeoxyuridine in anticancer chemotherapy. 375 35

At a nontoxic dose (50 microM), the two potent uridine phosphorylase inhibitors, benzylacyclouridine and benzyloxybenzylacyclouridine (BBAU), potentiated 5-fluoro-2'-deoxyuridine (FdUrd) growth inhibition of human pancreatic carcinoma (DAN) and, to a lesser extent, human lung carcinoma (LX-1) cells in culture. BBAU was more effective than benzylacyclouridine. BBAU (50 microM) enhanced the cytocidal effect of FdUrd (1 microM, 3 hr) on DAN grown on soft agar from 75 to 88%. In antithymocyte serum-immunosuppressed mice bearing DAN, the mean tumor weight in animals treated with FdUrd (50 mg/kg/day for 2 days) was 11% less than that of untreated controls. When BBAU (10 mg/kg/day for 2 days) was coadministered, the mean tumor weight at Day 10 was 78% less than untreated controls, with no apparent host toxicity, clearly demonstrating the potentiation of the antitumor effects of FdUrd by BBAU. The fact that DAN responded better than LX-1 to benzylacyclouridine and BBAU could be due, in part, to the lower relative activity of thymidine phosphorylase to uridine phosphorylase in DAN compared to LX-1. The activities of other enzymes involved in FdUrd metabolism, thymidine kinase, uridine kinase, orotate phosphoribosyltransferase, 5'-nucleotidase, and dihydrouracil dehydrogenase, did not differ between the two cell lines.
...
PMID:Potentiation of 5-fluoro-2'-deoxyuridine antineoplastic activity by the uridine phosphorylase inhibitors benzylacyclouridine and benzyloxybenzylacyclouridine. 623 86

The activities throughout the cell cycle of thymidine kinase (EC 2.7.1.21), dihydrothymine dehydrogenase (EC 1.3.1.2), thymidine phosphorylase (EC 2.4.2.4) and dTMP phosphatase (EC 3.3.3.35) were measured in the Epstein-Barr virally transformed human B lymphocyte line LAZ-007. Cells were synchronised at different stages of the cell cycle using the technique of centrifugal elutriation. The degree of synchrony in each cycle-stage cell population was determined by flow microfluorimetric analysis of DNA content and by measurement of thymidine incorporation into DNA. The activity of the anabolic enzyme thymidine kinase was low in the G1 phase cells, but increased manyfold during the S and G2 phases, reaching a maximum after the peak of DNA synthesis, then decreasing in late G2 + M phase. By contrast, the specific activities of the enzymes involved in thymidine and thymidylate catabolism, dihydrothymine dehydrogenase, thymidine phosphorylase and dTMP phosphatase remained essentially constant throughout the cell cycle, indicating that the fate of thymidine at different stages of the cell cycle is governed primarily by regulation of the level of the anabolic enzyme thymidine kinase and not by regulation of the levels of thymidine catabolising enzymes.
...
PMID:The activities of thymidine metabolising enzymes during the cell cycle of a human lymphocyte cell line LAZ-007 synchronised by centrifugal elutriation. 626 Jan 57

3-Cyano-2,6-dihydroxypyridine (CNDP) was identified as a potent inhibitor (IC50 value, 4.4 nM) of dihydrouracil dehydrogenase (DHUDase) [EC 1.3.1.2], a rate-limiting enzyme in 5-fluorouracil (5-FU) degradation. The inhibitory activity of CNDP was about 2,000 times that of uracil under our assay conditions. Kinetic analyses with partially purified enzyme from rat liver revealed that the mechanism of inhibition of DHUDase by CNDP was of mixed type with an inhibition constant (Ki) of 1.51 nM. CNDP had less effect on 5-FU phosphorylation than on 5-FU degradation. The inhibitory effect of CNDP on ribosylation of 5-FU was 600 to 1,000 times less than that on DHUDase. Moreover, CNDP did not inhibit uridine kinase, thymidine kinase, or pyrimidine phosphoribosyltransferase. Coadministration of CNDP with 1-ethoxymethyl-5-fluorouracil (EM-FU) to rats with Yoshida sarcoma elevated the level of 5-FU in both the blood and the tumor and enhanced the antitumor effect of EM-FU. These findings indicated that CNDP would be a useful chemical modulator in chemotherapy with 5-FU or its prodrugs.
...
PMID:3-Cyano-2,6-dihydroxypyridine (CNDP), a new potent inhibitor of dihydrouracil dehydrogenase. 813 51

5-Benzylbarbituric acid derivatives were synthesized as a series of new, specific, and potent inhibitors of uridine phosphorylase. Among these, 5-(m-benzyloxy)benzyl-1-[(2-hydroxyethoxy)methyl] barbituric acid (5-benzyloxybenzylbarbituric acid acyclonucleoside, BBBA) was found to be the most potent with Ki values of 1.1 +/- 0.2 and 2.6 +/- 0.3 nM with uridine phosphorylase from human and mouse livers, respectively. BBBA exhibited competitive inhibition with uridine phosphorylase from both human and mouse livers. The 5-benzylbarbituric acid derivatives are specific inhibitors of uridine phosphorylase, as they had no effect on thymidine phosphorylase (EC 2.4.2.4), thymidine kinase (EC 2.7.1.21), uridine-cytidine kinase (EC 2.7.1.48), orotate phosphoribosyltransferase (EC 2.4.2.10), orotidine 5'-monophosphate decarboxylase (EC 4.1.2.23), and dihydrouracil dehydrogenase (EC 1.3.1.2). These compounds are more potent, easier to synthesize, and have better water solubility than their uracil counterparts as inhibitors of uridine phosphorylase. Furthermore, the 5-benzylbarbituric acids were found to be better inhibitors of human uridine phosphorylase than the murine enzyme, whereas the reverse holds true for the 5-benzyluracil derivatives. The 5-benzylbarbituric acid derivatives have potential usefulness in the therapy of cancer and AIDS, as well as other pathological and physiological disorders.
...
PMID:5-Benzylbarbituric acid derivatives, potent and specific inhibitors of uridine phosphorylase. 821 79

This in vivo study examines the ability of 5'-amino-5'-deoxythymidine (5'-AdThd) to modulate 5-iododeoxyuridine (IdUrd) cellular metabolism in two human colon cancer xenografts (HT 29 and HCT-116), two actively proliferating normal mouse tissues (bone marrow and intestine), and a quiescent normal mouse tissue (liver). 5'-AdThd is a thymidine analogue that at low concentrations (<30 micrometer) can increase thymidine kinase activity, which is the rate-limiting enzyme for activation of IdUrd. We reported recently that the in vitro incubation of HT 29 and HCT-116 cells in 5'-AdThd + IdUrd resulted in an enhancement of 5-iodo-2'-dUTP pools, IdUrd DNA incorporation, and subsequent radiosensitization compared with incubation with IdUrd alone (Clin. Cancer Res., 1: 407-416, 1995). These in vitro effects were more significant in the radioresistant cell line HT 29. Using a 6-day continuous infusion of IdUrd (50 or 100 mg/kg/day) and/or 5'-AdThd (200 mg/kg/day), no increase in systemic toxicity (percentage of body weight loss) was observed in athymic nude mice with 5'-AdThd alone or when combined with IdUrd. There was significant dose-dependent, systemic toxicity with IdUrd, which was reversible within 3 days of completing the lower-dose IdUrd infusion. However, a comparison of plasma levels during the 6-day continuous infusion of IdUrd +/- 5'-AdThd showed a significant interaction of IdUrd and 5'-AdThd, resulting in higher plasma levels by day 6 of both compounds and the principal metabolites, iodouracil and deoxyuridine, which is consistent with nonlinear saturating effects on dihydrouracil dehydrogenase. Coadministration of IdUrd and 5'-AdThd resulted in an increase in the percentage of IdUrd DNA incorporation in the two proliferating normal tissues, which was significant only with the lower IdUrd dose. No effect on IdUrd DNA incorporation was found in normal liver at either IdUrd dose +/- 5'-AdThd. Similar to our in vitro data, the continuous infusion of IdUrd and 5'-AdThd showed a significant effect by increasing the percentage of IdUrd DNA incorporation in HT-29 xenografts at both IdUrd doses, whereas coadministration of 5'-AdThd had no such effect in HCT-116 xenografts.
...
PMID:In vivo modulation of iododeoxyuridine metabolism and incorporation into cellular DNA by 5'-amino-5'-deoxythymidine in normal mouse tissues and two human colon cancer xenografts. 981 59


1 2 Next >>

---