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)

N6-Benzyladenosine is a competitive inhibitor of adenosine deaminase from L-1210 cells in axenic culture as well as a potent antiproliferative agent in vitro and in vivo. Potentiation of the growth inhibitory activity of 9-beta-D-arabinosyladenine (ara-A) was observed in the L-1210 system with maximum synergism with a mixture of 16 micron ara-A and 10 micron benzyladenosine. Kinetic studies with L-1210 cell lysates showed values for Km of 0.25 mM ara-A and Ki of 0.23 mM benzyladenosine. It is suggested that ara-A and benzyladenosine in suitable combination may be expected to demonstrate enhanced clinical chemotherapeutic effectiveness.
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PMID:Synergism between the antiproliferative activities of arabinosyladenine and N6-benzyladenosine. 56 24

A number of 5'-(O-acyl) derivatives of 9-beta-D-arabinofuranosyladenine (ara-A, VIRA-A) (2a-k) were prepared by direct acylation of the parent nucleoside 1 in pyridine-N,N-dimethyliformamide. These compounds, designed as prodrugs for 1, offer a range of solubilities and lipophilicities indicating for several examples improved solubility and the potential for improved membrane transport over 1. All are resistant to deactivation by adenosine deaminase. Of special interest is the 5'-(O-valeryl) derivative 2d that shows a marked increase in antiviral activity over 1.
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PMID:Prodrugs of 9-beta-D-arabinofuranosyladenine. 1. Synthesis and evaluation of some 5'-(O-acyl) derivatives. 72 31

The endothelial surface of rabbit corneas was perfused with vidarabine monophosphate (with and without adenosine deaminase inhibitor), vidarabine (with and without adenosine deaminase inhibitor), and ara-Hx. In concentrations 10 times to 1,500 times higher than those that have been obtained in the aqueous humor following topical, subconjunctival, or systemic administration, none of the compounds had any effect on corneal endothelial cell function or ultrastructure for the duration of the experimental model.
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PMID:Effect of vidarabine and related compounds on corneal endothelium. 86 15

Tritium-labeled vidarabine was incubated with fresh citrated human blood in the absence and presence of an adenosine deaminase inhibitor, co-vidarabine was rapidly deaminated to form ara-Hx with minimal incorporation into the erythrocytes. Ara-HxMP was identified as the major component in the erythrocytic nucleotide pool, together with small amounts of IMP, adenosine nucleotides and traces of arabinosyl nucleotides. Addition of the inhibitor completely protected vidarabine from enzymatic deamination and resulted in much greater accumulation of vidarabine 5'-mono-, di-, and triphosphates in the erythrocytes.
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PMID:Effect of an adenosine deaminase inhibitor on the uptake and metabolism of arabinosyl adenine (Vidarabine) by intact human erythrocytes. 93 46

2'-Deoxycoformycin (2'-dCF), a potent inhibitor of adenosine deaminase, was tested in combination with 9-beta-D-arabinofuranosyladenine (ara-A) and 9-beta-D-arabinofuranosyladenine 5'-formate for cytotoxic activity against mouse leukemia L1210 in culture. 2'-dCF, which alone had no activity, significantly enhanced cytostatic and cytotoxic activities of ara-A and its more soluble derivative, 9-beta-D-arabinofuranosyladenine 5'-formate; the latter 2 agents, when tested at equimolar concentrations, were equivalent in their effects on proliferation and viability. The therapeutic response of mice bearing the in vitro line of L1210 cells (L1210/C2) to combination therapy with 2'-dCF and 9-beta-D-arabinofuranosyladenine 5'-phosphate was comparable to that reported elsewhere for therapy of mice bearing the parent in vivo line. Continuous exposure of cultured L1210 cells to ara-A and 2'-dCF induced a prolonged period of unbalanced growth, characterized by inhibition of proliferation and DNA synthesis while RNA and protein synthesis continued; exposure periods in excess of a single population doubling were required to achieve significant cell kill. Potentiation of ara-A activity against the relatively insensitive mouse leukemia L1210 was attributed to increased stability of ara-A resulting from 2'-dCF inhibition of adenosine deaminase.
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PMID:Enhancement of 9-beta-d-arabinofuranosyladenine cytotoxicity to mouse leukemia L1210 in vitro by 2'-deoxycoformycin. 94 95

Adenosine aminohydrolase from human spleen was purified 120 fold. In pH 7.3 phosphate buffer at 37 degrees, this enzyme preparation deaminated adenosine and arabinosyladenine (ara-A) with apparent values for the Michaelis constant of 40 muM and 90 muM respectively. The products of both deamination reactions, i.e., inosine and arabinosylhypoxanthine, were competitive inhibitors with Ki equal to 710 muM and 60 muM, respectively. N6-benzyladenosine and 2'-deoxy-N6-benzyladenosine were competitive inhibitors. The former was better able to inhibit ara-A than adenosine deamination, while the latter was equivalent in inhibiting deamination of these two substrates. Evidence for a naturally occurring adenosine aminohydrolase inhibitor in spleen was presented. It is suggested that benzyladenosine and deoxybenzyladenosine might potentiate ara-A chemotherapy of neoplasms and metastates in the spleen and other hemic cells.
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PMID:Adenosine aminohydrolase from human spleen: partial purification and some kinetic properties. 107 May 12

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

The metabolism of 6-dimethylaminopurine arabinoside (ara-DMAP), a potent inhibitor of varicella-zoster virus replication in vitro, was studied in rats and cynomolgus monkeys. Rats dosed intraperitoneally or orally with ara-DMAP excreted unchanged ara-DMAP and one major metabolite, 6-methylaminopurine arabinoside (ara-MAP), in the urine. They also excreted allantoin and small amounts (less than 4% of the dose each) of hypoxanthine arabinoside (ara-H) and adenine arabinoside (ara-A). The relative amount of each urinary metabolite excreted remained fairly constant for intraperitoneal ara-DMAP doses of 0.3 to 50 mg/kg of body weight. Rats pretreated with an inhibitor of microsomal N-demethylation, SKF-525-A, excreted more unchanged ara-DMAP and much less ara-MAP than did rats given ara-DMAP alone. Rats pretreated with the adenosine deaminase inhibitor deoxycoformycin excreted more ara-MAP and much less ara-H and allantoin. ara-MAP was shown to be a competitive alternative substrate inhibitor of adenosine deaminase (Ki = 16 microM). Rats given ara-DMAP intravenously rapidly converted it to ara-MAP and purine metabolism end products; however, ara-A generated from ara-DMAP had a half-life that was four times longer than that of ara-A given intravenously. In contrast to rats, cynomolgus monkeys dosed intravenously with ara-DMAP formed ara-H as the major plasma and urinary end metabolite. Rat liver microsomes demethylated ara-DMAP much more rapidly than human liver microsomes did. ara-DMAP is initially N-demethylated by microsomal enzymes to form ara-MAP. This metabolite is further metabolized by either adenosine deaminase, which removes methylamine to form ara-H, or by microsomal enzymes, which remove the second methyl group to form ara-A.
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PMID:Metabolism and pharmacokinetics of the anti-varicella-zoster virus agent 6-dimethylaminopurine arabinoside. 131 79

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

Seven 6-alkoxypurine arabinosides were synthesized and evaluated for in vitro activity against varicella-zoster virus (VZV). The simplest of the series, 6-methoxypurine arabinoside (ara-M), was the most potent, with 50% inhibitory concentrations ranging from 0.5 to 3 microM against eight strains of VZV. This activity was selective. The ability of ara-M to inhibit the growth of a variety of human cell lines was at least 30-fold less (50% effective concentration, greater than 100 microM) than its ability to inhibit the virus. Enzyme studies suggested the molecular basis for these results. Of the seven 6-alkoxypurine arabinosides, ara-M was the most efficient substrate for VZV-encoded thymidine kinase as well as the most potent antiviral agent. In contrast, it was not detectably phosphorylated by any of the three major mammalian nucleoside kinases. Upon direct comparison, ara-M was appreciably more potent against VZV than either acyclovir or adenine arabinoside (ara-A). However, in the presence of an adenosine deaminase inhibitor, the arabinosides of adenine and 6-methoxypurine were equipotent but not equally selective; the adenine congener had a much less favorable in vitro chemotherapeutic index. Again, this result correlated with data from enzyme studies in that ara-A, unlike ara-M, was a substrate for two mammalian nucleoside kinases. Unlike acyclovir and ara-A, ara-M had no appreciable activity against other viruses of the herpes group. The potency and selectivity of ara-M as an anti-VZV agent in vitro justify its further study.
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PMID:6-Methoxypurine arabinoside as a selective and potent inhibitor of varicella-zoster virus. 164 71


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