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:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enzyme inhibitors used to simulate the inherited immunodeficiency diseases, adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency, have been assessed in cultured human lymphocytes. Only 2'-deoxycoformycin (dCF) completely inhibited ADA in T and B cells at concentrations in excess of 5 microM. Erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) and 8-amino guanosine (8-NH2GR) did not inhibit ADA or PNP completely at any concentration. Detailed metabolic experiments comparing viability and deoxynucleotide accumulation showed that B cell lines of malignant origin also accumulated high levels of dATP from 2'-deoxyadenosine (dAR), and dGTP from 2'-deoxyguanosine (dGR) as effectively as T cells--even without inhibitors, however, dAR reduced cell viability only when ADA was inhibited by dCF, whilst dGR was equally toxic with or without inhibitor, even to a line which accumulated no dGTP. These experiments indicate that cultured lymphocytes, using either EHNA or 8-NH2GR as enzyme inhibitor, are not valid models of the toxicity to the immune system in inherited ADA or PNP deficiency. They demonstrate that the ability to accumulate high levels of dATP or dGTP is not exclusive to T cells and that the in vitro toxicity of dAR or dGR could relate to the use of excess substrate and/or accumulation in different nucleotide, not deoxynucleotide pools.
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PMID:B cells as well as T cells form deoxynucleotides from either deoxyadenosine or deoxyguanosine. 642 86

Several nucleoside analogues, some of which are potent inactivators of isolated S-adenosylhomocysteinase (AdoHcyase), were tested with respect to their effect on intracellular AdoHcyase and S-adenosylhomocysteine (AdoHcy) catabolism in intact rat hepatocytes. Among the analogues tested, 9-beta-D-arabinofuranosyladenine and 9-beta-D-arabinofuranosyl-3-deazaadenine were the most potent inactivators of intracellular AdoHcyase. Compounds like 2-chloroadenosine and carbocyclic adenosine are extremely efficient inactivators of the isolated enzyme, but these nucleosides exerted only a limited effect on the enzyme in intact hepatocytes. Only a moderate effect was observed with 2-chloro-3-deazaadenosine and 2'-deoxyadenosine, and a high concentration of 5'-deoxy-5'-methylthioadenosine was required to inactivate the enzyme. There was a correlation between inactivation and accumulation of AdoHcy. Carbocyclic-3-deazaadenosine caused no inactivation of AdoHcyase in liver cells but caused a massive accumulation of AdoHcy, suggesting that this analogue functions as a reversible inhibitor of the enzyme. Residual enzyme activity was observed with all the nucleoside analogues tested. The intracellular enzyme inactivated in the presence of 2'-deoxyadenosine and 9-beta-D-arabinofuranosyladenine was readily recovered when the cells were transferred to fresh medium containing adenosine deaminase, but reactivation of the enzyme activity after treatment of the cells with 2-chloroadenosine and 5'-deoxy-5'-methylthioadenosine was also observed. The inactivation of intracellular enzyme induced by 2-chloro-3-deazaadenosine, 9-beta-D-arabinofuranosyl-3-deazaadenine, and carbocyclic adenosine was essentially irreversible under the conditions of the experiments. Factors determining the effect of nucleoside analogues on intracellular AdoHcyase are discussed.
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PMID:Inactivation and reactivation of intracellular S-adenosylhomocysteinase in the presence of nucleoside analogues in rat hepatocytes. 646 91

The adenosine deaminase-resistant purine deoxynucleoside 2-chloro-2'-deoxyadenosine (CdA) is markedly toxic in vitro to nondividing and proliferating normal human lymphocytes and to many leukemia cell specimens. The CdA is also effective against mouse L1210 leukemia in vivo. The present investigations have examined the pharmacology, chemotherapeutic activity, and toxicity of CdA in nine patients with advanced hematologic malignancies refractory to conventional therapy. When administered by continuous intravenous infusion, the deoxyadenosine analog was well tolerated. As monitored by radioimmunoassay, plasma CdA levels rose gradually during the infusions. The CdA was not deaminated significantly. In all patients with leukemia, the CdA lowered the blast count by at least 50%. In one patient with a T-cell leukemia-lymphoma, and in another patient with chronic myelogenous leukemia in blast crisis, the CdA infusion eliminated all detectable blasts from the blood and bone marrow. In a patient with a diffuse lymphoma complicated by severe autoimmune hemolytic anemia, CdA treatment quickly terminated the hemolytic process. Bone marrow suppression represented the dose-limiting toxicity, and was related to plasma CdA levels, cumulative drug dosage, and the rapid release of CdA that accompanied tumor cell lysis.
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PMID:Antileukemic and immunosuppressive activity of 2-chloro-2'-deoxyadenosine. 658 95

A patient with refractory T-cell acute lymphoblastic leukemia was treated with eight courses of the adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF), over a 5-month period. After developing resistance to dCF, he responded to treatment with the combination of dCF and 9-beta-D-arabinofuranosyladenine (ara-A). We monitored the levels in plasma and urine of adenosine, 2'-deoxyadenosine, and ara-A as well as the accumulation of their nucleotide derivatives in erythrocytes and circulating lymphoblasts. We also monitored the activities of adenosine deaminase and S-adenosylhomocysteine (AdoHcy) hydrolase and the concentrations of AdoHcy and S-adenosylmethionine in lymphoblasts. Production of 2'-deoxyadenosine was related to both the duration of dCF infusion and the magnitude of cytolysis that occurred during treatment: much more 2'-deoxyadenosine was produced by dCF infusion when disease was active than by the same infusion given during remission. Resistance to dCF was associated with a decrease of greater than 90% in the amount of deoxyadenosine 5'-triphosphate accumulated by circulating lymphoblasts. Infusion of dCF resulted in increases of up to 20-fold in the concentration of AdoHcy in circulating lymphoblasts, causing a decrease in the S-adenosylmethionine:AdoHcy ratio (the "methylation index") from a pretreatment value of greater than 40:1 to less than 4:1. This ratio decreased to 2.5:1 during combined treatment with dCF and ara-A, which caused nearly complete inactivation of lymphoblast AdoHcy hydrolase. Decline in the methylation index was accompanied by inhibition of the methylation of newly synthesized lymphoblast RNA. Impaired ability to catabolize AdoHcy may have contributed to the cytolytic responses to dCF and ara-A, as well as to hepatic and central nervous system toxicity associated with their combined use.
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PMID:S-adenosylhomocysteine catabolism and basis for acquired resistance during treatment of T-cell acute lymphoblastic leukemia with 2'-deoxycoformycin alone and in combination with 9-beta-D-arabinofuranosyladenine. 660 86

The toxicity of the deoxyribonucleosides, 2'-deoxyadenosine, 2'-deoxyguanosine, and thymidine, for human T lymphoblasts is mediated by the accumulation of the corresponding deoxyribonucleoside triphosphate (dATP, dGTP, or dTTP, respectively). We have examined whether leukemic cells of non-T-cell origin are capable of accumulating deoxyribonucleotides in culture and whether this capability correlates with the activities of purine metabolizing enzymes in these cells. We have found that non-T, non-B acute lymphoblastic leukemia cells with low ecto-5'-nucleotidase and high adenosine deaminase activities increase their dATP pools by greater than tenfold when exposed to deoxyadenosine and an inhibitor of adenosine deaminase in culture. Cells from 2 of 9 patients with chronic lymphocytic leukemia and 4 of 11 patients with acute nonlymphoblastic leukemia achieved similar elevations in dATP, but there was no relationship between dATP accumulation and adenosine deaminase, purine nucleoside phosphorylase, or ecto-5'-nucleotidase activities. Treatment of four individuals with acute lymphoblastic leukemia with the adenosine deaminase inhibitor, 2'-deoxycoformycin, resulted in elevations in plasma deoxyadenosine concentrations and in increments in lymphoblast dATP levels that were similar to those measured in lymphoblasts cultured with deoxyadenosine and deoxycoformycin prior to treatment. In vitro incubations of leukemic cells with deoxyribonucleosides may provide a rational basis for the use of these compounds as chemotherapeutic agents.
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PMID:Deoxyribonucleoside triphosphate accumulation by leukemic cells. 660 41

Mice were given constant infusions of the adenosine deaminase inhibitor, 2'-deoxycoformycin, by i.p. implantation of microosmotic pumps, delivering the compound at a rate of 0.16 mg hr-1 kg-1. In accordance with published data, we observed that adenosine deaminase in most tissues was nearly completely inhibited. In addition, the S-adenosylhomocysteine hydrolase activity decreased slowly and showed a half-life in liver of about 4 hr. The rate and extent of the inactivation were highest in spleen. The amounts of adenosine, 2'-deoxyadenosine, S-adenosylhomocysteine, and S-adenosylmethionine were determined in treated animals and control animals. The tissue levels of adenosine and, to a lesser degree, S-adenosylhomocysteine and S-adenosylmethionine were critically dependent on the procedure used for processing the tissues. Lowest concentrations were observed when the organs were frozen in situ by liquid nitrogen. Treatment with 2'-deoxycoformycin induced no or a moderate increase in tissue content of adenosine and S-adenosylhomocysteine, whereas the amount of 2'-deoxyadenosine increased markedly, especially in spleen and thymus. 2'-Deoxycoformycin treatment caused an increase in adenosine and 2'-deoxyadenosine, but not S-adenosylhomocysteine, in serum of mice.
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PMID:Effect of 2'-deoxycoformycin infusion on S-adenosylhomocysteine hydrolase and the amount of S-adenosylhomocysteine and related compounds in tissues of mice. 660 64

The tight-binding adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF), was continuously infused into mice by intraperitoneal implantation of microosmotic pumps delivering the compound at a rate of 0.16 mg hr-1 kg-1 for up to 6 days. The activity of cerebral adenosine deaminase was nearly totally inhibited. The amount of adenosine and 2'-deoxyadenosine was determined in the brain frozen in liquid nitrogen through the intact skull bone. The concentration of adenosine was about 1 nmol/g, and was essentially not altered following treatment with deoxycoformycin. Deoxycoformycin induced a progressive increase in cerebral content of 2'-deoxyadenosine, which after 1 day of treatment equalled the amount of adenosine. The concentrations of serotonin, dopamine and noradrenaline in the brain were not altered.
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PMID:Neurotoxicity of deoxycoformycin: effect of constant infusion on adenosine deaminase, adenosine, 2'-deoxyadenosine and monoamines in the mouse brain. 660 84

Immunodeficient children who lack the purine metabolic enzyme adenosine deaminase have markedly elevated plasma concentrations of 2'-deoxyadenosine and adenosine. However, little information exists concerning the magnitude of endogenous 2'-deoxyadenosine and adenosine synthesis by normal human hematopoietic cells. In the present experiments, we have used the sensitive technique of high performance liquid chromatography to quantitate changes in 2'-deoxyadenosine and adenosine production during human lymphocyte mitogenesis. In the presence of the adenosine deaminase inhibitor deoxycoformycin, human T lymphocytes stimulated with phytohemagglutinin (PHA), and non-T lymphocytes stimulated with formalinized Staphylococcus aureus Cowan strain I, excreted 2'-deoxyadenosine into the cell medium. The nucleoside was detectable as early as 20 h after addition of mitogen. The time course of 2'-deoxyadenosine excretion correlated with the uptake of [methyl-3H]thymidine into nucleic acid. Mitogen-stimulated human lymphocytes produced only minimal amounts of adenosine. The results suggest that increased 2'-deoxyadenosine synthesis and release may normally accompany human lymphocyte mitogenesis.
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PMID:Changes in deoxyadenosine production during human lymphocyte mitogenesis. 660 41

9-beta-D-Arabinofuranosyl-2-fluoroadenine (2-F-ara-A) and 2-fluoro-2'-deoxyadenosine (2-FdAdo) were potent inhibitors of L1210 cell growth in culture. Even though these 2-fluoroadenine nucleosides are very poor substrates for adenosine deaminase, erythro-9-(2-hydroxyl-3-nonyl)adenine potentiated the growth-inhibitory properties of 2-FdAdo but not 2-F-ara-A in a synergistic manner. 2-FdAdo and 2-F-ara-A inhibited the conversion of [3H]cytidine to deoxycytidine nucleotides and incorporation into DNA, suggesting that ribonucleotide reductase was an intracellular site of action. 2-F-ara-A (6 microM) in combination with 2,3-dihydro-1H-pyrazole[2,3-a]imidazole gave synergistic inhibition of L1210 cell growth. At lower concentrations of 2-F-ara-A, the inhibition by this combination was only additive. The addition of Desferal to the combination of 2-F-ara-A plus 2,3-dihydro-1H-pyrazole[2,3-a]imidazole provided a strong synergistic combination. Similar results were obtained with combinations which included F-ara-A, hydroxyurea, and Desferal. The combinations of 2-FdAdo plus 2,3-dihydro-1H-pyrazole[2,3-a]imidazole or hydroxyurea gave strong synergistic inhibition of L1210 cell growth, even at the lowest concentration of 2-FdAdo (0.6 microM) studied. The presence of Desferal in the combination served to further potentiate the synergism.
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PMID:Synergistic inhibition of leukemia L1210 cell growth in vitro by combinations of 2-fluoroadenine nucleosides and hydroxyurea or 2,3-dihydro-1H-pyrazole[2,3-a]imidazole. 661 Nov 98

3'-Deoxyadenosine, 3'-amino-3'-deoxyadenosine (3'3'), nine derivatives therefrom, two derivatives of 5'-amino-5'-deoxyadenosine and three derivates of 3', 5'-dideoxyadenosine were tested in cell culture for antiviral activity against three DNA viruses: adenovirus 5, herpesvirus hominis 1, and vaccinia virus. Cytotoxicity was also assessed. (3'3') derivatives affected the multiplication of all three viruses similarly. Those which were effective were also cytotoxic at the same or slightly higher concentration. Substitution or other molecular modification of (3'3') tend to lower the biological activity. The presence of an adenosine deaminase inhibitor enhanced both antiviral activity against adenovirus 5 and cytotoxicity in (3'3') compounds, but not in the others. Both 5'-amino-5'-deoxyadenosine compounds were active against vaccinia virus only. Of the three 3', 5'-dideoxyadenosines, only one had both cytotoxic and antiviral activity. Most, if not all, seemingly antiviral effects appear to be caused by inhibition of the cell metabolism.
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PMID:Derivatives of 3'- and 5'-deoxyadenosine: their inhibitory activity against DNA viruses. 696 1


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