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

The distribution of arabinosylcytosine (ara-C) and its metabolites has been measured in the liver, small intestine, spleen, and kidney of mice inoculated ip 5-6 days earlier with L1210 leukemia cells. Two major metabolites were found in the tissues--the nucleotides and the deaminated inactive product, arabinosyluracil (ara-U). The decay curve of ara-C in most of these tissues was curvilinear; the ara-C half-lives estimated from the terminal phases were 8. 11, 12, and 12 hr for spleen, kidney, intestine, and liver tissues, respectively. The ara-C half-life was not correlated with the deoxycytidine deaminase activity in the tissues. However, the deaminase activity in vitro correlated well with the amount of ara-U present in vivo. Similar analyses were made for L1210 leukemic cells and ascites fluid. A high nucleotide level was found in the cells and a significant amount of nucleotides was also identifiable in the ascites fluid. The activities of deoxycytidine kinase, but not of deoxycytidine deaminase, in host tissues of mice inoculated with L1210 leukemic cells sensitive to ara-C were greater than in those of normal mice. The phosphorylating activities in vitro correlated with the amount of nucleotide present in vivo in mice bearing L1210 leukemic cells. However, the infiltration of leukemic cells containing high kinase activities into the host tissues accounted for most, if not all, of the nucleotide level in these tissues. This is further evidenced by the fact that inoculating mice with L1210 leukemic cells resistant to ara-C did not alter the kinase activity or nucleotide levels of the host tissues; these resistant cells contain negligible amounts of ara-C phosphorylating activities.
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PMID:Correlation of mouse tissue distribution of arabinosylcytosine in vivo with enzymatic activities in vitro. 0 36

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

A unique seven-membered heterocyclic-ring inhibitor of adenosine deaminase was studied. One preparation of the compound inhibited replication of herpes simplex virus in the absence of adenine arabinoside. In this capacity, the minimal inhibitory concentration of deaminase inhibitor for herpes simplex virus type 1 (HSV-1), with 50 percent reduction of plaque-forming units as the end point, was 37.7 mug/ml. This activity compared favorably with the inhibitory activity of ara-hypoxanthine (34.1 mug/ml). Another preparation of deaminase inhibitor lacked antiviral activity. On the other hand, the adenosine deaminase inhibitor was active at a concentration of 0.009 mug/ml as a potentiator of the inhibition of HSV-1 by adenine arabinoside. The potentiation of adenine arabinoside by deaminase inhibitor is about 4,000 times more potent than the activity of the direct inhibitory effect on HSV-1. The nature of the possible contaminant of the preparation in question is unknown. Coformycin, another inhibitor of adenosine deaminase, had no antiviral activity in the absence of adenine arabinoside.
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PMID:Antiviral activity of an adenosine deaminase inhibitor: decreased replication of herpes simplex virus. 16 17

The effect of ara-A on cellular growth, DNA synthesis, and RNA synthesis, and RNA synthesis was measured in an established cell line (B-mix K-44/6) devoid of adenosine deaminase activity. Cells adapted to growth in a medium supplemented with horse serum provided an environment totally lacking adenosine deaminase activity whereas cultivation of cells in a medium supplemented with calf serum provided a system capable of deaminating ara-A to ara-H (half-life = 14 hours). Under deaminase-free conditions early log phase cells underwent 1.5 population doublings during 28 hours compared with 0.25 doublings in the presence of 37 micronM ara-A. When cells were grown in medium supplemented with calf serum the additionof 37 to 225 micronM ara-A resulted in a cessation of mitosis for periods of 5 to 30 hours respectively. Following this quiescent period growth resumed at the original rate. With 600 micronM ara-A mitosis was reversibly inhibited up to 35 hours after drug addition. The effects of ara-A on RNA and DNA synthesis were monitored by continuously or pulse labeling B-mix K-44/6 cells with [3H]-uridine or [3H]thymidine. Ara-A did not influence RNA synthesis as judged by labeled uridine incorporation. Under deaminase-free conditions, 5.4 micronM ara-A inhibited labeled thymidine incorporation by 50%. In the presence of the enzyme, approximately twice the ara-A concentration was required for the same inhibition; furthermore the initial inhibition was followed by a partial recovery in the rate of thymidine incorporation. Examination of thymidine incorporation. Examination of thymidine nucleotide pools during ara-A treatment revealed to changes in the labeling of dTMP, dTDP, and dTTP. Thus inhibition of [3H]thymidine incorporation by ara-A accurately reflected inhibition of DNA synthesis. We conclude that, in spite of an initial inhibition of DNA synthesis and mitosis by ara-A, B-mix K-44/6 cells recover from the inhibitory effects if the drug is removed either by a change in the culture medium or by metabolism to ara-H.
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PMID:Antiproliferative effects of 9-beta-d-arabinofuranosyladenine in a mammalian cell line devoid of adenosine deaminase activity. 19 68

In conventional clinical use, cytosine arabinoside (ara-C) is rapidly deaminated by pyrimidine nucleoside deaminase to the nontoxic compound uracil arabinoside. Tetrahydrouridine (THU) effectively inhibits this enzymatic degradation but is by itself nontoxic. This study demonstrates that concomitant administration of THU markedly increases the myelosuppressive potency of ara-C. When 25 or 50 mg/kg of THU iv and 0.1--0.2 mg/kg of ara-C iv are given daily x 5 days, they produce moderate-to-severe leukopenia and mild-to-moderate thrombocytopenia. A dose of 25 mg/kg of THU with 0.1 mg/kg of ara-C iv daily x 5 days appears appropriate for phase II studies; it produces myelosuppression equivalent to that produced by 3 mg/kg/day x 5 days of ara-C alone. No toxicity occurred with this combination that would not have been expected from ara-C given alone in an equitoxic dose. Although THU and ara-C produced a reduction in peripheral blood and bone marrow blast cells in eight of nine patients with acute leukemia, bone marrow remission did not occur in any of these heavily pretreated patients.
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PMID:Phase I evaluation of tetrahydrouridine combined with cytosine arabinoside. 38 91

[14C]-tetrahydrouridine (THU), a strong inhibitor of cytidine (CR) deaminase, was, after iv administration, rapidly and quantitatively cleared from the blood with a plasma half-life of about 1 hour. The main pathway of excretion was through the kidneys: most of a dose of 50 mg/kg was excreted within 12 hours and excretion was essentially complete within 48 hours. Oral administration of the same dose revealed absorption of about 10% from the gastrointestinal tract. THU at 10, 25, and 50 mg/kg given 15 minutes before [3H]-cytosine arabinoside (ara-C) at a dose of 0.003 mg/kg produced about a two fold increase in ara-C blood levels at all times measured from 5 minutes to 4 hours, with only slight increases in the half-life of ara-C. A dose-related effect of THU upon the deamination of ara-C was obvious only during the time from 15 minutes to 1 hour after the injection of 3H-ara-C. The inhibitory effect of THU upon CR deaminase was also reflected in a considerably increased ratio of ara-C/uracil arabinoside in the urine.
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PMID:Tetrahydrouridine: Physiologic disposition and effect upon deamination of cytosine arabinoside in man. 58

The 6C3HED lymphosarcoma, a tumor cell line very sensitive to 9-beta-D-arabinofuranosyladenine (ara-A), and 6C3HED/ara-A, a line resistant to ara-A, were studied. Both were responsive to 9-beta-D-arabinofuranosylcytosine (ara-C). Two lines of cells. L1210 and L1210/ara-C, are both resistant to ara-A and have very high levels of the deaminase that inactivates ara-A. When an effective inhibitor of the deaminase, 2'-deoxycoformycin, was combined with ara-A in the treatment of mice bearing L1210 or L1210/ara-C tumors, both became responsive to ara-A. Studies are reported on the extent of effects of 2'-deoxycoformycin at several dose levels and the duration of its effect in tumor cells and normal tissues. Single doses produce essentially complete inhibition of the deaminase, and little recovery was seen before 24 hr. However, DNA synthesis in normal tissues recovered more quickly. It is suggested that ara-A and ara-C, the former as a new derivative (9-beta-D-arabinofuranosyladenine 5'-phosphate) and possibly combined with 2'-deoxycoformycin, be regarded as potentially alternative drugs for the treatment of neoplasms.
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PMID:Enhancement of the antitumor activity of arabinofuranosyladenine of 2'-deoxycoformycin. 94 95

An integrated mathematic computer-based model of the pharmacokinetics, intracellular enzyme kinetics, and cell kinetics of the treatment of L1210 leukemia by cytosine arabinoside (ara-C) is described. The compartment model of Bischoff and Dedrick is extended to the intracellular level by inclusion of equations describing the phosphorylation, dephosphorylation, and deamination of ara-C with enzymatic feedback control. The activities of kinase, deaminase, and phosphatase are explicitly included in the models and are estimated from relevant data. Cell proliferation is described by a continuous-flow mathematic model in which cellular maturation and cell-to-cell variability in maturation rates are key variables. Cell proliferation is related to intracellular biochemistry through mathematic expressions which relate cell lethality and progression delay to the time course of intracellular ara-CTP. In vitro and in vivo experiments performed in a number of laboratories are compared by simulation. The most sensitive parameters in dose-response and cell-survival simulations are deoxycytidine kinase activity, ara-CTP half-life, renal clearance of ara-C, and cell-kinetic parameters for proliferation and cell killing. Progression delay is vital to the realistic simulation of divided-dose schedules. By comparative simulation we have identified areas of uncertainty which can be classified by a few additional measurements. The applications of simulations combining pharmacokinetic, biochemical, and cell-kinetic data in vitro and in vivo are discussed, exploring consistency among different measurements, and relating experimental protocols to clinical treatment.
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PMID:Computer simulation of leukemia therapy: combined pharmacokinetics, intracellular enzyme kinetics, and cell kinetics of the treatment of L1210 leukemia by cytosine arabinoside. 102 30

The phosphorylation of 1-beta-D-arabinofuranosylcytosine (ara-C) was studied in cell-free extracts from a variety of solid mouse tumors, L1210 ascites and in normal liver and spleen. Two apparent Michaelis constants were observed for kinase activity in Lewis lung (Km1, 4.15 muM; Km2 58.1 muM), sarcoma 180 (Km1 6.66 muM; Km2 56.18 muM), adenocarcinoma 755 (Km1 4.34 muM; Km2 50.0 muM) and l1210 (Km1 29.41 muM; Km2 41.67 muM). The Km1 values generally ranged from 5 to 20 muM 3H-ara-C while the Km2 values ranged from 20 to 60 muM 3H-ara-C. Normal spleen (Km 47.6 muM), normal liver (Km 10.0 muM) and Ridgway osteogenic sarcoma (Km 31.2 muM) had single Km values. In the presence of tetrahydrouridine (H4U), the in vitro phosphorylation of ara-C was increased as much as 91% in cell-free extracts from adenocarcinoma 755; lesser increases were observed in other tumor extracts. At low substrate concentrations, the apparent Km decreased or did not change in the presence of H4U, while at higher substrate concentrations the apparent Km was increased or did not change in the presence of H4U. In the presence of H4U, Vmax for kinase activity increased most in those tumors possessing deaminase activity.
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PMID:Influence of tetrahydrouridine on the phosphorylation of 1-beta-D-arabinofuranosyl-cytosine (ara-C) by enzymes from solid tumors in vitro. 105 9

Deamination of many analogs of adenine nucleosides results in the loss of their chemotherapeutic efficacy. Two approaches have been used in this study to overcome this problem. First, some adenine nucleotides, which are resistant to mammalian adenosine deaminase, are more toxic to animal cells than are the respective nucleosides. For toxic to animal cells than are the respective nucleosides. For example, 9-beta-D-arabinofuranosyladenine 5'-phosphate, a molecule that penetrates the cell without degradation, has a more sustained toxicity against mouse fibroblasts (L-cells) than does 9-beta-D-arabinofuranosyladenine (ara-A). Furthermore, L-cells treated with 2',3'-dideoxyadenosine 5'-phosphate are extensively killed after 48 hr, whereas 2',3'-dideoxyadenosine is almost nontoxic to L-cells. Specific inhibition of adenosine deaminase by nontoxic concentrations of erythro-9-(2-hydroxy-3-nonyl)adenine greatly potentiates the biological activity of both ara-A and 3'-deoxyadenosine (cordycepin). Simultaneous administration of cytostatic concentrations of ara-A and the inhibitor of adenosine deaminase to L-cells killed greater than 99.9 percent of cells in 36 hr. A similar concentration of ara-A plus the deaminase inhibitor also markedly extended the mean survival of mice bearing Ehrlich ascites carcinoma as compared to ara-A alone. A cytostatic concentration of cordycepin 1 x 10-4 M), administered in the presence of deaminase inhibitor, killed greater than 99.9 percent of cultured L-cells in only 8 hr. During the latter incubation, accumulation of uridine in acid-insoluble material reached a maximum after 30 min, and incorporation of thymidine into acid-insoluble material was almost totally arrested after 2 hr.
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PMID:Two approaches that increase the activity of analogs of adenine nucleosides in animal cells. 107 75


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