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)

Minimum inhibitory concentrations of 9-beta-D-arabinofuranosyladenine (ara-A, adenine arabinoside, vidarabine) and a purified preparation of 9-beta-D-arabinofuranosylhypoxanthine (arabinoslhypoxanthine, ara-Hx) at end points of 50% MIC50) and 100% (MIC100) reduction to challenges of approximately 50 p.f.u. of herpes simplex virus, type 1 (HSV-1) were determined in vero renal tissue cultures. Adenosine deaminase is universally present in tissue cultures and serum. These same tests were repeated in the presence of a potent inhibitor of adenosine deaminase, R-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo-4,5-d)-(1,3)-diazepin-8-ol (co-vidarabine, co-ara-A). Addition of co-ara-A to assays of MIC50 or MIC100 for ara-A ensures standard reproducible results which can be compared in different laboratories. After incubations of HSV-1 in infected cultures for 96 hours, 35 degrees C., with concentrations of ara-A or ara-Hx at the MIC100 and over, cells were scraped and sonicated. Supernates were then reinoculated into vero flasks free of antiviral agents to determine minimum lethal concentrations (MLC's). Standard values (microng/ml.) for ara-A with co-ara-A are 11.3 (MIC50), 17.0 (MIC100), and 34.0 (MLC) but are 68.1 (MIC50), 170.4 (MIC100) and 375 (MLC) for ara-Hx. These data confirm that as a virustatic agent (MIC100) ara-A is 10 times more active than ara-Hx. Ara-A and ara-Hx have virucidal potentials which require approximately two times the respective MIC100.
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PMID:Inhibitory and lethal concentrations of 9-beta-D-arabinofuranosyladenine and its hypoxanthine-derivative versus herpes simplex virus, type 1. 19 46

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

The rational design of antitumor and antiviral agents must ultimately take advantage of biochemical differences between normal host cells and transformed cells. The initial experiments must be performed with subcellular or cellular model systems. For the studies with arabinosyl nucleosides we have chosen those enzyme systems, synthesizing DNA and RNA; being precursor analogues, the different arabinosyl nucleosides have been added in the triphosphate state to the different DNA- and RNA polymerase assays. 1-beta-D-Arabinofuranosylcytosine-5'-triphosphate has been found to inhibit the RNA-dependent DNA polymerases (isolated from oncogenic RNA viruses) 200-fold more sensitively than viral and cellular DNA-dependent DNA polymerases. Recent results, showing that RNA-leukemia-virus-related sequences are present in DNA of some human leukemia patients might support the assumption that the efficacy of this antimetabolite in the treatment of acute leukemia is due to its, at least relative selective inhibitory activity on reverse transcriptase. 9-beta-D-Arabinofuranosyladenine-5'-triphosphate is a strong inhibitor of cellular DNA polymerases with the cytological consequence of an inhibition of cell proliferation. The clinical benefit of the compound in treatment of tumors is dependent on their levels of adenosine deaminase. The triphosphate of this compound is a 100-fold more sensitive inhibitor of the herpesvirus DNA polymerase compared to the cellular replicative DNA polymerase. In addition the analogue, incorporated into herpesvirus DNA, acts as chain terminator. These effects are the biochemical basis for the highly selective antiherpesvirus activity of this antimetabolite. The anomer 9-alpha-D-arabinofuranosyladenine-5'-triphosphate only inhibits cellular replicative DNA polymerase and has no effect on herpesvirus DNA polymerase. Consequently this agent acts only cytostatically and not antivirally. Concerning 1-beta-D-arabinofuranosyluracil and 1-beta-D-arabinofuranosylthymine no pronounced antitumor or antiviral effect is known.
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PMID:Rational design of arabinosyl nucleosides as antitumor and antiviral agents. 61 2

Forty-nine children with recurrent acute lymphoblastic leukemia (ALL) were entered into a randomized Phase II trial evaluating 2'-deoxycoformycin (dCF) alone or in combination with adenine arabinoside (ara-A). 2'-Deoxycoformycin is an inhibitor of adenosine deaminase (ADA), an enzyme found in relatively high amounts in malignant lymphoid cells. Ara-A inhibits DNA polymerase and DNA synthesis. Because its efficacy in vivo as an anticancer agent is limited by its rapid inactivation by ADA, ara-A was combined with dCF to produce cytoreductive levels of ara-A. Twenty-four patients were assigned to receive dCF alone and 25 to receive the combination. No patient responded to dCF alone, and one patient developed a complete remission after treatment with the combination. The toxicity of dCF alone was minimal, except for one patient who became obtunded on day 5 following the first cycle of therapy. In contrast, five patients developed severe toxicity with the combination, including renal failure (three patients), hepatic failure (three patients), and neurologic toxicity (two patients). These results indicate that, at the doses and schedule used in this study, the combination of dCF and ara-A has significant toxicity and minimal activity against recurrent ALL in children.
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PMID:Lack of significant activity of 2'-deoxycoformycin alone or in combination with adenine arabinoside in relapsed childhood acute lymphoblastic leukemia. A randomized phase II trial from the Childrens Cancer Study Group. 144 10

Adechlorin exhibiting a potent inhibitory activity against calf intestinal adenosine deaminase was isolated from the cultured broth of Actinomadura sp. OMR-37. The molecular formula was C11H15N4O4Cl. The aglycone of adechlorin was identical with that of the known adenosine deaminase inhibitors coformycin and 2'-deoxycoformycin. Adechlorin did not exhibit inhibitory activity against various bacteria and fungi at 1.0 mg/ml. The Ki values for adechlorin, coformycin and 2'-deoxycoformycin against adenosine deaminase were determined to be 5.3 X 10(-10) M, 2.1 X 10(-10) M and 7.6 X 10(-11) M, respectively. Adechlorin as well as coformycin and 2'-deoxycoformycin enhanced the antiviral activity of Ara-A. The acute toxicity of adechlorin in mice was less than those of coformycin and 2'-deoxycoformycin.
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PMID:Adechlorin, a new adenosine deaminase inhibitor containing chlorine production, isolation and properties. 384 Jan 53

1 The cardiovascular actions of 23 adenosine analogues have been examined in anaesthetized open thorax dogs; the analogues were substituted in the 2-position of the purine ring, or in the exocyclic amino group, or were modified in the imidazole or sugar rings.2 The effects of these compounds on coronary blood flow, peripheral blood pressure, and heart rate were compared with those of adenosine.3 9-beta-D-Arabinofuranosyladenine had no cardiovascular action; the other analogues on intra-atrial administration caused an immediate increase in coronary blood flow, the magnitude and duration of which varied with the structures of the analogues.4 2-Fluoro-, 2-bromo-, 2-isobutylthio-, 2-ethylamino-, and 5'-deoxy-5'-chloro- adenosines had coronary dilator potencies equal to or greater than that of adenosine. No relationship was found between the dilator potency of the adenosine analogues and their duration of coronary dilator action.5 The coronary dilator action of adenosine was potentiated by inosine, 9-beta-D-arabinofurano-syladenine, tubercidin, N(6)-methyladenosine and 2-trifluoromethyl-N(6)-methyladenosine.6 There was no correlation between the substrate specificities of the shorter-acting analogues for adenosine deaminase or adenosine kinase and their duration of coronary dilator action.7 It is proposed that in the anaesthetized dog, uptake into tissues is a more important mode of removal of adenosine and adenosine analogues from the vascular system than inactivation by adenosine deaminase, that the duration of coronary dilator action of the analogues is related primarily to their specificity for the carrier which mediates adenosine uptake, and that the adenosine carrier is not associated with kinase action.
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PMID:Studies on the coronary dilator actions of some adenosine analogues. 436 49

9-beta-D-Arabinofuranosyladenine (ara-A), 9-beta-D-arabinofuranosyladenine 5'-monophosphate, and 9-beta-D-arabinofuranosyladenine 5'-triphosphate competitively inhibit both the synthesis and hydrolysis of S-adenosylhomocysteine catalyzed by S-adenosylhomocysteinase [S-adenosylhomocysteine hydrolase (EC 3.3.1.1)] from mouse liver, and the inhibitor constants were 5.0 X 10(-6), 1.1 X 10(-4), and 1.0 X 10(-3) M, respectively. A time-dependent inactivation of the enzyme was observed when the enzyme was preincubation with ara-A, 9-beta-D-arabinofuranosyladenine 5'-monophosphate, or 9-beta-D-arabinofuranosyladenine 5'-triphosphate. ara-A was the most potent inactivator. The inactivation with ara-A was less pronounced in the presence of adenosine, S-adenosylhomocysteine, adenine, adenosine 5'-monophosphate, or adenosine 5'-diphosphate, showed first-order kinetics, saturability, and irreversibility. The rate of inactivation was half-maximal at 5 X 10(-6) M ara-A, and the rate constant of inactivation was 0.43 min-1 at saturating concentrations of ara-A. ara-A was tightly but not covalently bound to the enzyme. ara-A bound to the enzyme was not available for deamination to 9-beta-D-arabinofuranosylhypoxanthine catalyzed by the enzyme adenosine deaminase.
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PMID:Interaction of 9-beta-D-arabinofuranosyladenine, 9-beta-D-arabinofuranosyladenine 5'-monophosphate, and 9-beta-D-arabinofuranosyladenine 5'-triphosphate with S-adenosylhomocysteinase. 616 Sep 9

Adenine arabinoside (ara-A) at a concentration of 5-10 micrograms/ml inhibited the multiplication of two Epstein-Barr virus (EBV) producer lymphoblastoid cell lines B . 95-8 and P3HR-1. The nonproducer EBV genome carrier cell line, Raji, and the EBV negative cell line, Ramos, were not significantly affected. The cytotoxicity of ara-A to Ramos, Raji and P3HR-1 cells increased in the presence of 1 . 10(-5)M erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an inhibitor of adenosine deaminase. EHNA alone was noncytotoxic and even had a mild stimulatory effect on cell multiplication. The level of adenosine deaminase in Raji and Ramos cells was similar to that observed in human cord blood lymphocytes, as determined by starch gel electrophoresis. A low level of adenosine deaminase was detected in P3HR-1 cells and the enzyme was absent from B . 95-8 cells. These findings indicate that in the absence of adenosine deaminase, ara-A cytotoxicity increased. Ara-A (5 micrograms/ml) and EHNA (1 . 10(-5)M) had no effect on human cord blood lymphocytes stimulated by phytohemagglutinin as measured by (3H) thymidine uptake, but had some effect on protein A-stimulated lymphocytes. Ara-A, however, inhibited the transformation of human cord blood lymphocytes by EBV, which EHNA did not inhibit. The synthesis of EBV capsid antigen in B . 95-8 cells was also inhibited by ara-A and slightly stimulated by EHNA.
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PMID:Cytotoxicity of arabinofuranosyladenine and erythro-9-(2-hydroxy-3-nonyl) adenine to Epstein-Barr virus producer and nonproducer lymphoma cells in culture. 630 55

A deficiency of adenosine deaminase, an enzyme important in purine nucleoside catabolism, is associated with a severe combined immunodeficiency disease in children. Inhibition of this enzyme in vitro and in vivo results in an impairment in lymphoblast proliferation. We have investigated the pharmacologic inhibition of this enzyme by 2'-deoxycoformycin in 15 patients with hematologic malignancies. Biochemical consequences of the administration of this agent were closely monitored in erythrocytes, nucleated peripheral blood and bone marrow cells, serum, and urine. A marked rise in erythrocyte dATP was accompanied by a depletion of ATP in those patients exhibiting toxicity. Most patients excreted large amounts of deoxyadenosine but not adenosine in the urine. Serum deoxyadenosine rose in patients demonstrating a marked decrease in cell mass. The biochemical disturbances and clinical toxicity, including hepatic, renal, and conjunctival abnormalities, were usually reversible. Central nervous system toxicity, which potentially was the most serious consequence, was associated with high erythrocyte dATP/ATP ratios and high levels of cerebrospinal fluid deoxyadenosine. In patients with lymphoma and leukemia, objective responses were observed but were short-lived. Patients with chronic lymphocytic leukemia receiving weekly low doses of the drug demonstrated minimal toxicity and some efficacy. The chemotherapeutic potential o 2'-deoxycoformycin, as either a single agent or in combination with Ara-A, merits further exploration.
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PMID:The biochemical and clinical consequences of 2'-deoxycoformycin in refractory lymphoproliferative malignancy. 697 50

9-beta-D-Arabinofuranosyladenine (ara-A) inactivates isolated S-adenosyl-L-homocysteine (AdoHcy) hydrolase (EC 3.3.1.1) as well as AdoHcy hydrolase in intact cells. Whereas the inactivation in cell-free systems is an irreversible process, the AdoHcy hydrolase activity in rat hepatocytes exposed to ara-A gradually recovered upon prolonged incubation of the cells in a medium devoid of ara-A. This process, tentatively termed reactivation of the enzyme, was nearly totally dependent on a high level of adenosine deaminase in the extracellular medium, which induced a decrease in intracellular content of adenosine as well as ara-A. Reactivation of intracellular enzyme was inhibited by adenosine deaminase inhibitors [2'-deoxycoformycin and erythro-9-(2-hydroxy-3-nonyl)adenine] and the synthetic substrate for AdoHcy hydrolase, 3-deazaadenosine. An inhibitor of protein synthesis (cycloheximide) was without effect. Homocysteine, which protected the intracellular AdoHcy hydrolase against inactivation by ara-A, induced no reactivation of the enzyme. The half-life of the intracellular ara-A-AdoHcy hydrolase complex was about 90 min and was not affected by adenosine deaminase, 3-deazaadenosine, or homocysteine added to the cell suspension. However, the rate of elimination of the complex in the hepatocytes exceeded the rate of reactivation of AdoHcy hydrolase. Thus, the elimination process accounted for the reactivation, but not correlation between these two processes was observed. Reactivation of intracellular AdoHcy hydrolase caused a pronounced fall in cellular content of AdoHcy. The possibility that reduced cellular level of AdoHcy induced the reactivation of AdoHcy hydrolase seemed unlikely. This statement was based on the observation that reactivation was observed also under conditions of high concentrations of AdoHcy (obtained by the addition of homocysteine to the cell suspension). Reactivation of AdoHcy hydrolase with a concomitant decrease in cellular level of AdoHcy could also be demonstrated with mouse plasmacytoma (MPC-11) cells and mouse fibroblasts (L-929) exposed to ara-A, but the reactivation process was far less pronounced than with hepatocytes.
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PMID:Reactivation of S-adenosylhomocysteine hydrolase activity in cells exposed to 9-beta-D-arabinofuranosyladenine. 697 84


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