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)

Leung, Hazel Barner (University of Pennsylvania School of Medicine, Philadelphia), Alice McGovern Doering, and Seymour S. Cohen. Effect of 9-beta-d-arabinofuranosyladenine on polymer synthesis in a polyauxotrophic strain of Escherichia coli. J. Bacteriol. 92:558-564. 1966.-Adenine-requiring mutants have been obtained from Escherichia coli strain 15 TAU, which also needs thymine, arginine, and uracil for growth. Some of these are killed by 9-beta-d-arabinofuranosyladenine (ara-A) in the absence of exogenous adenine; a particular mutant of this type, designated TAUAd, has been used in our studies. The lethality of ara-A, d-arabinosylhypoxanthine, and the 1-n-oxide of ara-A has been compared; ara-A is equally toxic in the presence or absence of thymine. Although the absence of uracil reduces ara-A toxicity, the lack of arginine almost eliminates lethality. It was found that ara-A completely inhibits deoxyribonucleic acid synthesis without markedly affecting ribonucleic acid (RNA) synthesis. Some inhibition of protein synthesis can be detected. However, the interpretation of these results is complicated because (i) exogenous adenine must be excluded, (ii) endogenous adenine is made available from RNA turnover, and (iii) ara-A is being rapidly converted to only slightly less toxic arabinosylhypoxanthine by the adenosine deaminase of E. coli. A suitable inhibitor for the bacterial deaminase has not yet been found.
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PMID:Effect of 9-beta-D-arabinofuranosyladenine on polymer synthesis in a polyauxotrophic strain of Escherichia coli. 533 77

The metabolism of 9-beta-D-arabinofuranosyladenine (ara-A, vidarabine) and its effects on DNA synthesis were compared in uninfected and herpes simplex virus type-1 (HSV-1)-infected KB cells. In the absence of an inhibitor of adenosine deaminase, ara-A was deaminated to 9-beta-D-arabinofuranosylhypoxanthine and phosphorylated to ara-A-5'-mono-, di- and triphosphates in both types of cells. When an inhibitor of adenosine deaminase (coformycin) was added to cell cultures, nucleotides were the only metabolites detected--primarily the 5'-triphosphate of ara-A (aATP). Detailed studies performed in the presence of coformycin established that the net rate and extent of aATP formation were the same in uninfected and HSV-1-infected cells. After a 12-hr exposure to 50 microM ara-A, intracellular concentrations of aATP were approximately 40 microM. Levels of aATP correlated directly with inhibition of total DNA synthesis. Approximately 0.7 microM aATP was required for 50% inhibition of total DNA synthesis in both uninfected and HSV-1-infected cells. Following removal of ara-A-containing culture medium, aATP levels in uninfected cells declined with a half-life of 3.2 hr. In marked contrast, the half-life in HSV-1-infected cells was 9.3 hr; this may explain why as little as a 3-hr exposure to ara-A resulted in a significant HSV-1 titer reduction. Taken together, the data show that when ara-A was removed from culture medium, levels of aATP persisted longer in HSV-1-infected cells thereby prolonging antiviral activity. This effect could be important in vivo where levels of ara-A oscillate with dosing schedule.
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PMID:Metabolism of arabinosyladenine in herpes simplex virus-infected and uninfected cells. Correlation with inhibition of DNA synthesis and role in antiviral selectivity. 608 27

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

The effect of the adenosine deaminase inhibitor, 2'-deoxycoformycin, on cellular nucleotides during therapy with continuous infusion of 9-beta-D-arabinofuranosyladenine (ara-A) has been investigated. In three courses of treatment using increasing doses, the active 5'-triphosphate of ara-A, 9-beta-D-arabinofuranosyladenine 5'-triphosphate (ara-ATP) accumulated in leukemic cells and erythrocytes from a patient treated for acute lymphocytic leukemia in proportion to the dose of ara-A. The cellular ara-ATP concentration increased more than 5-fold after the injection of a single, nontoxic, but pharmacologically active dose of 2'-deoxycoformycin 24 hr after initiation of ara-A infusion. However, this response was associated with a concomitant increase in the cellular deoxyadenosine triphosphate concentrations to levels equal to or greater than those of ara-ATP throughout the three treatment courses studied. Consistent with previous results using cell-free systems, it was demonstrated that a competitive relationship exists between deoxyadenosine triphosphate and ara-ATP for the inhibition of DNA synthesis in cultured human lymphoblastoid cells and that the ratio of the cellular concentrations of these nucleotides could predict the extent of inhibition of DNA synthesis. Application of this rationale to the nucleotides in the leukemic cells of the patient suggested that administration of 2'-deoxycoformycin may create a cellular biochemical milieu that could be antagonistic to the inhibition of DNA synthesis by ara-ATP.
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PMID:Modulation of 9-beta-D-arabinofuranosyladenine 5'-triphosphate and deoxyadenosine triphosphate in leukemic cells by 2'-deoxycoformycin during therapy with 9-beta-D-arabinofuranosyladenine. 617 7

The severity of herpetic keratitis induced by 9-(2-hydroxyethoxymethyl) guanine-resistant strains of herpes simplex virus was significantly reduced by cotherapy with 9-beta-D-arabinofuranosyladenine (ara-A) and 2-deoxycoformycin. Therapy with 5-trifluoromethyl-2'-deoxyuridine (F3TdR) significantly reduced the severity of keratitis induced by an acyclovir-resistant strain with a defective DNA polymerase. Therapy with 3 percent acyclovir ointment slightly reduced the number of herpetic lesions produced by either deoxypyrimidine kinase or DNA polymerase defective viruses, despite these viruses being 100 to 1000 times more resistant to acyclovir than the wildtype strain. Therapy with 3 percent ara-A ointment alone significantly reduced the severity of lesions produced by the wildtype herpes strain. Therapy with ara-A alone did not reduce the severity of disease induced by any of the acyclovir-resistant mutants. The sensitivity of the wildtype and mutant viruses to nucleoside analogs was confirmed by yield-reduction assays conducted with Vero cells. These studies indicate that cotherapy with ara-A and an adenosine deaminase inhibitor was a reasonable alternative therapy for keratitis due to mutants resistant to therapy with nucleoside analogs which require the virus-specified deoxypyrimidine kinase or DNA polymerase, while ara-A alone was not an effective alternative.
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PMID:Chemotherapy of herpetic keratitis induced by acyclovir-resistant strains of herpes simplex virus type 1. 628 20

Combinations of Virazole plus arabinofuranosylhypoxanthine (ara-Hx) and Virazole plus arabinofuranosyladenine (ara-A) were investigated in KB or BHK cells infected with types 1 or 2 herpes viruses. Combinations of Virazole and ara-Hx exhibited significant synergy as evaluated graphically (isobolograms) or by fractional inhibitory concentration (FIC) indices. Optimal ratios for the combination were 1:1 to 1:10 for Virazole to ara-Hx. At these ratios, FIC indices in the range of 0.5-0.2 were commonly observed. Combinations of Virazole and ara-A were antagonistic when observed in the presence of pentostatin, an adenosine deaminase inhibitor. In the absence of pentostatin, the minimum inhibitory concentration (MIC) of ara-A and degree of synergy with Virazole were variable.
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PMID:Evaluation of the anti-herpesvirus drug combinations: virazole plus arabinofuranosylhypoxanthine and virazole plus arabinofuranosyladenine. 629 75

Ara-C at very low dosage has been reported to decrease the host toxicity of ara-AMP or ara-A in combination with 2'-deoxycoformycin, a potent adenosine deaminase inhibitor, while increasing the toxicity to intracerebral L1210 leukemia. The possibility of increasing the selectivity of ara-A by prior administration of ara-C is explored. The importance of deoxynucleoside kinases, some of which may be cancer-induced, in obtaining selective anticancer effects is discussed. The possibility of a conformational basis for the differing degrees of selectivity and activity of various novel arabinosyl nucleosides is evaluated. The levels of cyclic nucleotides, which have opposing effects on leukemia, may possibly be manipulated to interfere with the growth of cancer cells. Approaches to minimizing major metabolic distortions, such as the progressive accumulation of dATP associated with the use of potent adenosine deaminase inhibitors and which limit the therapeutic effects of ara-A, are proposed.
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PMID:Biochemical and biophysical approaches to improving the anticancer effectiveness of Ara-adenine. 629 45

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

Accumulation of intracellular deoxyadenosine triphosphate and inactivation of the enzyme S-adenosylhomocysteine hydrolase by deoxyadenosine have been suggested as molecular mechanisms for lymphoid toxicity of inherited or acquired deficiency of adenosine deaminase. The relative roles of these two deoxyadenosine-mediated effects for lymphotoxicity have been explored by employing mutant human T- and B-lymphoblasts deficient in either adenosine kinase, deoxycytidine kinase, or both. At low concentrations (less than 25 mumol/L) of deoxyadenosine or ara-adenine, deoxycytidine kinase deficiency decreases growth sensitivity of human T-lymphoblasts to deoxyadenosine approximately fourfold, and to ara-adenine approximately twofold. Loss of both activities completely eliminates deoxyadenosine phosphorylation and cellular dATP accumulation, and decreases deoxyadenosine growth sensitivity approximately 200-fold and ara-adenine sensitivity approximately 80-fold. The inactivation by deoxyadenosine of intracellular S-adenosylhomocysteine hydrolase activity of human adenosine deaminase-deficient B-lymphoblasts and wild-type or deoxycytidine kinase-deficient T-lymphoblasts is comparable, despite the differing toxicity of this compound for these cell lines. Adenosine kinase deficiency in T-lymphoblasts results in resistance to 2'-deoxyadenosine--but not ara-adenine--associated inactivation of S-adenosylhomocysteine hydrolase, and this compound produces comparable degrees of inactivation of S-adenosylhomocysteine hydrolase in both the wild-type and double mutant cells, despite markedly different growth sensitivity. For B-lymphoblasts, 2'-deoxyadenosine together with adenosine produces comparable growth inhibition of wild-type and adenosine kinase-deficient cells, and this inhibition is more marked than with adenosine alone, but is independent of S-adenosylhomocysteine hydrolase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:S-adenosylhomocysteine hydrolase inactivation and purine toxicity in cultured human T- and B-lymphoblasts. 633 Feb 51

We sought to define the cellular activity that mediates resistance in human leukemic cells (CCRF-CEM) to the nucleoside 9-beta-D-arabinofuranosyladenine (ara-A). Stable mutants were obtained by continuous selection at ara-A concentrations of 1 or 2.5 microM in the presence of the adenosine deaminase inhibitor 2'-deoxycoformycin. Four clones selected for further investigation were 4- to 11-fold less sensitive to the cytotoxicity of ara-A than the parental CCRF-CEM line. These clones also showed cross-resistance to deoxyadenosine and thymidine, but normal sensitivity to arabinosylcytosine and adenosine, and increased sensitivity to the etoposide VP16-213. No change was found in the activity of kinases that phosphorylate ara-A and the various nucleosides that could account for the resistant phenotype in these mutant lines. Resistance was associated with a 2- to 8-fold increase in the level of all four deoxyribonucleoside triphosphates. The triphosphate pools in the mutants were resistant to the inhibition produced in wild-type cells by addition of deoxy-adenosine or thymidine, although significant activation in the deoxyguanosine triphosphate pool was obtained by higher concentrations of thymidine. An examination of ribonucleotide reductase in extracts of two of the mutants revealed a specific alteration in the normal sensitivity of the enzyme for deoxyadenosine triphosphate and adenosine triphosphate but not 9-beta-D-arabinofuranosyladenine 5'-triphosphate. When the level of ribonucleotide reductase activity was measured, it was found that the ara-A-resistant cells contained approximately twice the wild-type level of cytidine diphosphate reductase activity at physiological adenosine triphosphate level. This combination of increased enzyme activity and alteration in sensitivity to the nucleoside triphosphates could account for both the changes in deoxyribonucleotide pool sizes and the resistant phenotype of the presumed mutants.
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PMID:Selection of 9-beta-D-arabinofuranosyladenine-resistant human T-lymphoblasts with altered ribonucleotide reductase activity. 638 Jul 7


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