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)

2'-Deoxycoformycin (dCF), a tight-binding inhibitor of adenosine deaminase, has recently been entered into clinical trials. Toxicity has included lymphopenia, seizures, coma, conjunctivitis, renal failure, and hemolysis. Mice treated with dCF on a variety of schedules exhibited massive hemolysis. Hemolysis was brief, lasting about 20 hours, and did not recur upon readministration of the drug unless readministration was delayed for at least 6 days after initial exposure, which suggests that a sensitive subpopulation of cells was selectively destroyed. Splenectomy failed to protect the animals from dCF-induced hemolysis. Administration of adenosine or 2'-deoxyadenosine without dCF did not cause hemolysis, and use of these two agents with dCF did not potentiate the observed hemolysis. ATP and dATP levels were measured in erythrocytes, and changes in levels of these nucleotides did not correspond with the development of hemolysis.
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PMID:2'-Deoxycoformycin-induced hemolysis in the mouse. 697 51

Deoxycoformycin (dCF) is a specific inhibitor of adenosine deaminase (ADA). Rat hepatoma cells deficient in adenosine kinase and growing on adenosine as the sole carbon source are sensitive to the lethal action of dCF. Mutants resistant to dCF arise spontaneously with a frequency of 1.7 x 10(-6). This frequency is increased to 2.6 x 10(-5) by prior mutagenesis with ethyl methane sulfonate. Initially, dCF-resistant cell lines have 3-10 times the level of adenosine deaminase when compared to sensitive parental cells. Subsequent selection of mutants resistant to increased concentrations of dCF results in cells with a 15- to 30-fold increase in ADA levels. Quantitative immunoprecipitation tests indicate that the increase in enzyme activity in one line tested is due to an increase in the number of ADA molecules. These dCF' cell lines may serve as a model system to study the human disease state, hereditary hemolytic anemia, which is associated with increased levels of ADA.
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PMID:Isolation of deoxycoformycin-resistant cells with increased levels of adenosine deaminase. 698 55

Adenosine and deoxyadenosine toxicity was examined in colony assay systems for human T lymphocytes, B lymphocytes, and granulocytes. In the absence of deoxycoformycin, an adenosine deaminase inhibitor, no growth inhibition was observed in the three systems with concentrations of adenosine or deoxyadenosine of at least 200 microM. Deoxycoformycin itself had no growth-inhibitory effect at concentrations of at least 10 micrograms/ml. Combinations of deoxycoformycin (1 microgram/ml) and either adenosine or deoxyadenosine gave growth inhibition in all three systems. Deoxyadenosine was the most toxic in all the systems, the LD50 values being 20-25 microM. The LD50 values for adenosine were 45-55 microM. There was no evidence of selective toxicity by adenosine or deoxyadenosine with these three colony assay systems. In the T-lymphocyte colony system deoxyadenosine appeared to be toxic to both the inducer/helper and the suppressor/cytotoxic T-lymphocyte subpopulations.
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PMID:Adenosine and deoxyadenosine toxicity in colony assay systems for human T-lymphocytes, B-lymphocytes, and granulocytes. 698 86

2'-deoxycoformycin (2'-dCF) is a powerful inhibitor of adenosine deaminase (ADA), an enzyme found in high concentrations in lymphoid tissue. Although inactive in preclinical tumor models, 2'-dCF has shown clinical antitumor activity as a single agent in lymphoid malignancies. This drug has the added potential of being useful as a potentiator of other antitumor agents which are deactivated by ADA. It is also possible that the drug has potential as an immunosuppressive agent. Phase I studies are ongoing and phase II trials are planned to define the antitumor spectrum of this agent.
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PMID:2'-deoxycoformycin. A new anticancer agent. 701 25

Pentostatin, a potent inhibitor of adenosine deaminase, is an antineoplastic agent which has been studied in the treatment of a variety of lymphoproliferative disorders. It is particularly effective in the treatment of hairy cell leukaemia, achieving complete remissions in 33 to 92% of patients, and has useful activity in treating B cell chronic lymphocytic leukaemia, prolymphocytic leukaemia, adult T cell leukaemia/lymphoma and cutaneous T cell lymphoma refractory to conventional chemotherapy. Initial results suggest that in the treatment of hairy cell leukaemia pentostatin achieves a more rapid response and higher frequency of complete remission with longer duration than interferon-alpha 2a, although it is still not known if some patients experiencing complete remission have been cured. The drug has yet to be directly compared with other promising purine analogues such as cladribine and fludarabine, and results of such comparisons are required before the ultimate role of pentostatin in the treatment of hairy cell leukaemia can be clearly established. However, pentostatin does produce a substantial response in a difficult therapeutic area and should be considered for initial treatment of hairy cell leukaemia.
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PMID:Pentostatin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in lymphoproliferative disorders. 750 51

Pentostatin (2-deoxycoformycin) is a potent inhibitor of adenosine deaminase and has been demonstrated to augment endogenous adenosine levels during regional and global myocardial ischemia. Based on the rationale that increasing endogenous adenosine during ischemia may be cardioprotective, the objective of this study was to determine if adenosine deaminase inhibition with pentostatin could improve postischemic contractile dysfunction (stunning) in open-chest anesthetized dogs. All animals underwent 15 min of coronary occlusion followed by 3 h of reperfusion preceded by an intravenous bolus of either 0.2 mg/kg of pentostatin (n = 8) or saline (n = 7). Sonomicrometers were placed in the ischemic area and were used to measure systolic wall thickening before, during, and after occlusion of the left anterior descending artery. Myocardial blood flow was measured with tracer labeled microspheres at baseline, 10 min of occlusion and at 1 h of reperfusion. Both groups were equally dyskinetic during occlusion (-21 +/- 5% of baseline thickening in the controls and -28 +/- 8% in the pentostatin group). The pentostatin group, however, demonstrated better contractile function at all time points during reperfusion, which was significantly different from the control group at 3 h of reperfusion. The improvement in regional function in the pentostatin group was not due to significant disparities in hemodynamic variables, size of the region at risk, or in collateral blood flow. These results indicate that pentostatin can ameliorate the severity of myocardial stunning, an effect we propose is due to increasing endogenous levels of adenosine during the ischemic interval. Although significant improvement was detected with pentostatin, the improvement was modest compared to controls, suggesting that the utility of inhibiting adenosine deaminase to modify regional mechanical stunning is limited.
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PMID:Effect of adenosine deaminase inhibition with pentostatin on myocardial stunning in dogs. 764 20

Human adenosine deaminase (ADA) cDNA was randomly mutagenized in vitro and bacterial transformants were selected for resistance to the potent enzyme inhibitor, pentostatin (dCF). Cells transformed with mutant plasmids dCF-R2 and dCF-R6 were able to grow in the presence of 10(-6) M dCF, whereas 10(-11) M dCF blocked growth of cells complemented with wild-type ADA. DNA sequence analysis revealed double G/A conversions mutating Lys11 and Gln255 in dCF-R2, and Gly 31 and Glu 99 in dCF-R6, to different amino acids. Located far from the enzyme active site, these substitutions did not greatly affect the Km or Ki of the enzyme but were predicted to destabilize interactions within the enzyme structure. Mutants such as these may be useful to analysis of the stereology of inhibitor binding to ADA and toxicity of dCF.
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PMID:Mutagenesis of human adenosine deaminase to active forms that partially resist inhibition by pentostatin. 773 7

Pentostatin, an adenosine deaminase inhibitor, has been approved for the treatment of refractory hairy cell leukemia. In a preclinical toxicity study, Wistar rats were administered 0, 1, 10, 25, and 50 mg/kg (0, 6, 60, 150, and 300 mg/m2, respectively) pentostatin intravenously once a week for 26 wk (1.5-75-fold above the therapeutic dose in humans). Lymphoplasmacytic thyroiditis was present in 20% of females given 25 mg/kg and in 20 and 47% of males and females given 50 mg/kg, respectively. Thyroiditis was still present 4 wk following drug withdrawal. Thyroiditis was characterized by glandular enlargement, follicular epithelial hyperplasia and degeneration, colloid depletion, and interstitial infiltrates of lymphocytes and plasma cells. Drug-related changes in other tissues included lymphoid depletion of T-cell regions of thymus, spleen, and lymph nodes; bronchiolization of alveolar ducts with accumulation of mucus and foamy macrophages; testicular atrophy with sperm granulomas; dermoepidermal lymphocytic infiltrates with ulceration and alopecia; and hepatocytomegaly.
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PMID:Subchronic toxicity of pentostatin in Wistar rats. 789 80

The anti-human immunodeficiency virus agents 2',3'-dideoxyadenosine (ddAdo) and 2'-beta-fluoro-2',3'-dideoxyadenosine (2'-beta-F-ddAdo) are rapidly converted, both in vitro and in vivo, to the corresponding inosine analogs by the widely distributed enzyme adenosine deaminase (EC 3.5.4.4). We have determined the effects of the potent adenosine deaminase inhibitor 2'-deoxycoformycin (2'-dCF) on ddAdo and 2'-beta-F-ddAdo metabolism in MOLT-4 cells and on ddAdo antiviral activity in the ATH8 test system. At levels as low as 5 nM in the incubation medium, 2'-dCF effectively blocks the extracellular deamination of both agents, thus permitting their rapid cellular uptake as the unchanged parent compounds, rather than as the less lipid-soluble 2',3'-dideoxyinosine or 2'-beta-fluoro-2',3'-dideoxyinosine. The result is a significant increase in intracellular levels of the pharmacologically active forms 2',3'-dideoxyadenosine-5'-triphosphate and 2'-beta-fluoro-2',3'-dideoxyadenosine-5'-triphosphate. The effect becomes maximal over the range of 50-250 nM 2'-dCF and declines to control levels when extracellular 2'-dCF levels exceed 1 microM. This decrease in ddAdo and 2'-beta-F-ddAdo phosphorylation with higher levels of the inhibitor appears to result from intracellular penetration of 2'-dCF and consequent inhibition of intracellular deamination, a critical step in the activation of both agents through the 5'-nucleotidase pathway. In anti-human immunodeficiency virus assays, a 2.2-fold increase in ddAdo antiviral potency was seen at 2'-dCF levels of 20 and 50 nM.
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PMID:Enhancement by 2'-deoxycoformycin of the 5'-phosphorylation and anti-human immunodeficiency virus activity of 2',3'-dideoxyadenosine and 2'-beta-fluoro-2',3'-dideoxyadenosine. 796 62

The effect of 2-chloroadenosine, stable adenosine analog, and deoxycoformycin, adenosine deaminase inhibitor on brain ATP level and Na-K ATPase activity in ischemia were studied. The brain ATP level was increased after we administered both 2-chloroadenosine and deoxycoformycin, but Na-K ATPase activity did not change after deoxycoformycin. The results suggest that 2-chloroadenosine treatment influenced both the ATP production and membrane permeability due to cerebral ischemia. Deoxycoformycin did not protect the membrane permeability, although it increased the ATP production.
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PMID:The effects of 2-chloroadenosine and deoxycoformycin on the ATP level, Na-K ATPase activity in experimental brain ischemia of gerbil. 887 54


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