Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.4 (deaminase)
 5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deoxycytidine kinase, which phosphorylates deoxycytidine (CdR) and its analog, cytosine arabinoside (ara-C), has been purified 71-fold from human leukemic cells. Biochemical properties of the partially purified enzyme included a molecular weight of 68,000, Kms of 7.8 muM for CdR and 25.6 muM for ara-C, and optimal activity with ATP and GTP as phosphate donors. Ara-C phosphorylation was strongly inhibited by CdR (Ki = 0.17 muM) and dCTP (Ki = 7.3 muM) and was weakly inhibited by ara-CTP (Ki = 0.13 mM). Purification by calcium phosphate gel elution and DEAE chromatography effectively separated this enzyme from cytidine deaminase, which deaminates both CdR and ara-C, and from uridine-cytidine kinase, the enzyme which phosphorylates 5-azacytidine. CdR kinase activity was found to decrease and cytidine deaminase to increase with maturation of normal and leukemic granulocytes. Myeloblasts purified by Ficoll sedimentation revealed an average kinase activity of 15.4 U/mg protein in acute myelocytic leukemia and 12.3 U/mg protein in blastic crisis of chronic myelocytic leukemia (CML). The average ratio of CdR kinase to deaminase activity in crude cell extracts varied from 0.197 in AML and 0.089 in blastic crisis to 0.0004 in normal granulocytes, reflecting the changes which take place with cellular maturation. The absolute levels of kinase and deaminase and the ratio of these two enzymes varied considerably among patients with AML, indicating that quantitative differences may be found in the metabolism of CdR and its analogs in leukemic cells.
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PMID:Deoxycytidine kinase: properties of the enzyme from human leukemic granulocytes. 5 55

In this study we investigated the Ara-CTP-forming capacity of leukemic cells in different phases of the cell cycle. Cells from two leukemic cell lines and leukemic bone marrow cells from patients and rats (BNML model) with acute myelocytic leukemia were separated according to cell cycle phase by means of an albumin density gradient in a specially designed sedimentation chamber. We found that the activity of CdR kinase and Cyt deaminase is much less influenced by cell-cycle phase progression than TdR kinase activity. For the leukemic cell lines HL-60 and BNML-CL/O CdR kinase activity is even independent of cell-cycle phase. In addition, Ara-CTP formation is not restricted to cells in S-phase. Cell cycle phase-independent Ara-CTP formation creates a situation in which cells which are not in S-phase during exposure to Ara-C might undergo the cytotoxic effects of Ara-C as soon as they enter S-phase.
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PMID:Deoxycytidine kinase, thymidine kinase and cytidine deaminase and the formation of Ara-CTP in leukemic cells in different phases of the cell cycle. 215 90

The patients with cartinomatous peritonitis were treated with the intraperitoneal administration (ip) of N4-behenoyl-1-beta-D-arabinofuranosylcytosineine (BH-AC: analogue of Ara-C), and the pharmacokinetics of BH-AC ip was studied. The following results were obtained (1) Immediately after ip administration, the concentration of BH-AC in ascites became as high as 10(6) ng/ml. At 24 hours following BH-AC ip, 10(4) ng/ml of BH-AC was detected in ascites. (2) Immediately after ip administration the concentration of Ara-C derived from BH-AC in ascites became as high as 10(3) ng/ml. At 24 hours, more than 10 ng/ml of Ara-C was detected in the ascites. (3) Ara-U in ascites was detected also soon after BH-AC ip was performed. Accordingly, it is expected that deaminase may be present in ascites. (4) As compared with in ascites, Ara-C in plasma showed very low level (less than 1 ng/ml). These findings indicate that BH-AC is suitable drug for intraperitoneal administration, because BH-AC revealed low peritoneal and high plasma clearances.
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PMID:[Pharmacokinetics of N4-behenoyl-1-beta-D-arabinofuranosylcytosine after intraperitoneal administration]. 317 41

Ara-C should be converted to ara-CTP to inhibit DNA polymerase in the malignant cells but is rapidly inactivated to uracil arabinoside (ara-U) by cytidine deaminase in human tissue. Therefore, production as well as maintenance of ara-CTP in the cells is a function of both phosphorylation and deamination of ara-C, but is more dependent on the latter, because the deamination is several times superior to the former in terms of enzymatic activities. In chemotherapy with ara-C, the rate of the inactivation should be estimated for evaluating antitumor effect of the agent. Determination of serum or plasma deaminase activity can be a useful parameter of the inactivation. Attempts have been made to enhance the antitumor activity of ara-C by preventing deamination and a number of ara-C derivatives resistant to the deamination such as cyclocytidine, ara-C-5'-ester and acyl ara-C have been introduced. Cyclo-C gradually receives non-enzymatic hydrolysis to produce ara-C in neutral medium, which is useful for maintaining plasma ara-C level. Acyl ara-C such as behenoyl-ara-C (BHAC) is well incorporated into the cells and is highly distributed to lipophilic components such as membrane, microsome and mitochondria in the cells. The extremely gradual conversion of BHAC to ara-C in the cells is considered to be useful for maintaining effective intracellular concentration. A part of BHAC could be phosphorylated before deacylation. After intravenous administration of BHAC, the plasma drug concentrations are maintained significantly longer than those after the administration of the equivalent dose of ara-C. Therefore, BHAC is more resistant to the deamination than cyclo-C and the antitumor effect of the former is suspected to be milder but prolonged than that of ara-C or cyclo-C.
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PMID:[Chemotherapy of the malignancies from the viewpoint of pharmacology and biochemistry of cytosine arabinoside (ara-C) and its derivatives]. 619 11

Ara-C phosphorylation and Ara-C deamination was measured in vitro, using intact marrow myeloblasts from 25 patients with previously untreated acute myeloid leukaemia. At Ara-C concentrations above 10 microM there was no longer a linear relationship of phosphorylation to Ara-C concentration. Ara-U production was measured by sampling the incubation medium. This method showed greater Ara-U production than previous methods sampling the cell pellet alone. However, Ara-CTP/Ara-U ratios from intact myeloblasts were much higher than those recorded in studies using lysed myeloblasts. Using 1 microM Ara-C, a concentration representative of in vivo concentrations, deamination and phosphorylation were related to therapeutic response to Ara-C-containing drug regimens. There was no significant correlation of these variables with response, although 5/16 non-responders had low Ara-C phosphorylation (less than 1.5 pmol/10(6) cells/45 min/l pm Ara-C) compared with 0/9 responders. Measuring deaminase activity did not help in selecting non-responders. Even in patients with low phosphorylation increasing Ara-C concentration increased Ara-CTP levels proportionally, but up to 10 times conventional doses may be necessary to exceed endogenous dCTP levels.
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PMID:The relationship of Ara-C metabolism in vitro to therapeutic response in acute myeloid leukaemia. 695 91

While on therapy for acute myeloid leukemia, a 15-year-old girl developed extensive punctate keratitis of both eyes following high-dose cytarabine therapy (HD-Ara-C). Pharmacokinetic monitoring showed an increase of the Ara-C plasma levels up to twice the steady-state level within 10 minutes after discontinuation of the Ara-C infusion. Calculations of Ara-C plasma half-life, plasma clearance and volume of distribution were within the expected range. Owing to the short half-life of Ara-C in blood due to rapid deamination, varying infusion velocities will result in markedly varying plasma levels. Higher peak plasma levels lead to proportionally higher diffusion into compartments like tears, aqueous humor and cerebrospinal fluid. In compartments which lack noteworthy deaminase activity, dose intensity will be much more enhanced than in plasma. Peak plasma levels, therefore, may be associated with multifold local toxicity without concurrent increase of hematological toxicity. Especially when the drug is given in small volumes of infusion, these considerations should be taken into account. Precise control of infusion parameters and application of artificial tears for dilution of the Ara-C concentration on the corneal surface should be part of keratitis prophylaxis.
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PMID:Is there a relationship between cytarabine pharmacokinetics and keratitis?--A case report. 831 60

To establish the most effective and reasonable mode of combining and administrering ara-C with other antileukemic agents in chemotherapy for acute leukemia, the action mechanisms of ara-C was investigated in terms of intracellular pharmacodynamics and the biochemical action mechanism of ara-C was investigated in leukemic cell. Rensonable methods of administering the agent was considered as follows. 1. A low level of ara-C in the incubation medium induced a higher concentration of ara-CTP in leukemic cells. Therefore, maintenance of even a low plasma ara-C level after ara-C therapy could enhance the antileukemic effect of the agent. 2. Ara-C activation was increased in the presence of 6MP by suppressing elevation of deaminase activity in the cell suspection medium. Therefore, administration of 6MP prior to ara-C therapy could enhance the antileukemic effect of the agent. 3. Ten micrograms/ml of ara-C, corresponding to intermediate dose ara-C therapy, induced rapid endonuclease activation, DNA ladder fragmentation and subsequent apoptosis in large numbers of leukemic cells, suggesting that intermediate dose ara-C therapy is effective in reducing residual leukemic cells after therapy. 4. Blood transfusion for patients with high grade anemia prior to bebenoyl ara-C therapy prolonged higher and longer plasma drug maintenance. 5. Flowcytometry of cell cycle progression of L1210 cells treated by ara-C and daunorubicin revealed that a combination of ara-C first and daunorubicin second was superior to the reverse sequential combination. These improvements in the mode of administering ara-C could provide better results following chemotherapy for leukemia.
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PMID:Intracellular pharmacodynamics of ara-C and flowcytometric analysis of cell cycle progression in leukemia chemotherapy. 920 53

1-beta-D-Arabinofuranosylcytosine (ara-C) is used empirically at a low, conventional, or high dose. Ara-C therapy may be optimal if it is directed by the clinical pharmacokinetics of the intracellular active metabolite of ara-C, 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP). However, ara-CTP has seldom been monitored during low- and conventional-dose ara-C therapies because detection methods were insufficiently sensitive. Here, with the use of our newly established method (Cancer Res., 56, 1800 -- 1804 (1996)), ara-CTP was monitored in leukemic cells from acute myelogenous leukemia patients receiving low- or conventional-dose ara-C [subcutaneous ara-C administration (10 mg / m(2) ) (3 patients), continuous ara-C infusion (20 or 70 mg / m(2) / 24 h) (7 patients), 2-h ara-C infusion (70 mg / m(2) ) (4 patients), and 2-h infusion of N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine, a deaminase-resistant ara-C derivative (70 mg / m(2) ) (6 patients)]. Ara-CTP could be determined at levels under 1 microM. There was a close correlation between the elimination half-life values of the plasma ara-C and the intracellular ara-CTP. The presence of ara-C in the plasma was important to maintain ara-CTP. The continuous ara-C and the 2-h N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine infusions maintained ara-CTP and the plasma ara-C longer than the subcutaneous ara-C or the 2-h ara-C infusion. They also afforded relatively higher ara-CTP concentrations, and consequently produced ara-CTP more efficiently than the 2-h ara-C infusion. Different administration methods produced different quantities of ara-CTP even at the same dose.
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PMID:Monitoring of intracellular 1-beta-D-arabinofuranosylcytosine 5'-triphosphate in 1-beta-D-arabinofuranosylcytosine therapy at low and conventional doses. 1137 64