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)

Inhibition of adenosine deaminase activity leads to decreased cellular immunity. The effect of deoxycoformycin (DCF), a potent inhibitor of adenosine deaminase, on the ability of mouse spleen cells to generate antibody responses in vitro has been examined. With either continuous exposure to or pretreatment of the cells with deoxycoformycin, there was a decrease in cell survival and an increase in antibody-producing cells in the surviving cell population. To identify the cell population most susceptible to the inhibitor, the spleen was separated into B-cell, and T-cell, and macrophage components and each population was pretreated with deoxycoformycin before combination with its complementary treated or untreated population. Deoxycoformycin pretreatment had no effect on macrophages or B cells; however, pretreatment of the T cells resulted in increased antibody responses. When T cells and B cells were both pretreated and combined, there was a synergistic increase in the antibody response. In addition, supernatants from cultures in which both B cells and T cells had been pretreated with DCF were capable of enhancing antibody responses in cultures containing DCF-treated T cells. Though adenosine was increased in the stimulatory culture supernatants, adenosine alone did not enhance antibody responses in either untreated or DCF-treated cultures.
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PMID:Inhibition of adenosine deaminase leads to enhanced antibody responses in the mouse. 634 98

2'-Deoxycoformycin (DCF) is a potent inhibitor of adenosine deaminase (ADA) and a potential antineoplastic and immunosuppressive agent. In this study the kinetics of ADA expression was assessed by immunomorphologic and enzymatic methods in tissues of ACI rats given injections of DCF. The rats received a daily ip injection of 10 mg DCF/kg for 3 consecutive days. This treatment destroyed cortical thymocytes, whereas lymphocytes of the thymic medulla were mainly preserved. In control phosphate-buffered saline-injected rats, cortical thymocytes were not affected morphologically and displayed strong ADA staining. It was found unexpectedly that injections of DCF produced activation and, possibly, differentiation of B-cells in the mesenteric lymph nodes and spleen. These activated B-lymphocytes and plasma cells stained strongly for ADA. Transient changes in patterns of ADA expression were also observed in endothelial cells of blood vessels and liver Kupffer's cells, but these changes were not accompanied by degeneration of the cells. The treatment with DCF did not result in any permanent abnormalities in the rat tissues.
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PMID:Morphologic changes and immunohistochemical localization of adenosine deaminase in tissues of rats given injections of 2'-deoxycoformycin. 635 8

2'-Deoxycoformycin, a tight-binding adenosine deaminase inhibitor, was administered to 11 adult patients with refractory lymphoproliferative diseases. Total doses ranged from 1.0 to 13.5 mg/kg. Inhibition of lymphoblast adenosine deaminase was obtained in all cases and tumor cytoreduction was noted in eight of ten cases, but no clinically meaningful remissions were obtained. Major toxicities occurred in five patients and included pulmonary edema, renal failure, central nervous system toxicity, hypotension, and death. Toxicity prevented retreatment in several cases in which marked cytoreduction occurred. Deoxyadenosine triphosphate accumulated to a variable extent in the red blood cells of all patients, and a reciprocal decrease in erythrocyte adenosine triphosphate was noted in all cases but one. All patients who suffered major organ toxicity had red blood cell deoxyadenosine triphosphate/adenosine triphosphate ratios greater than 1.3. These data suggest that the degree of replacement of adenosine triphosphate by deoxyadenosine triphosphate in erythrocytes reflects the biochemical milieu which may result in systemic toxicity following treatment with 2'-deoxycoformycin.
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PMID:Alterations in erythrocyte adenine nucleotide pools resulting from 2'-deoxycoformycin therapy. 660 Jun 52

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

Rats implanted with EEG and EMG electrodes were treated with deoxycoformycin (0.5 or 2.0 mg/kg, i.p.), and polygraphically recorded for 6 h. Deoxycoformycin is a potent inhibitor of adenosine deaminase and would be expected to elevate the levels of adenosine in the central nervous system. The 0.5 mg/kg dose of the drug increased REM sleep and reduced REM sleep latency while the dose of 2.0 mg/kg increased deep slow-wave sleep (S2). These results appear to be consistent with those reported previously for the adenosine analog, N6-(L-phenylisopropyl)-adenosine (L-PIA) and indicate a hypnotic role for adenosine.
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PMID:Hypnotic effects of deoxycorformycin in rats. 660 61

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

Deoxycoformycin-resistant rat hepatoma cells exhibit up to a 2000-fold increase in adenosine deaminase activity compared to the sensitive parental cells. The increased enzyme activity in these cells is accompanied by similar increases in 1) the amount of adenosine deaminase protein, 2) the relative rate of adenosine deaminase synthesis in vivo, and 3) adenosine deaminase mRNA activity. To further investigate the mechanism(s) responsible for the overproduction of adenosine deaminase in these cells, we have isolated a recombinant plasmid containing a 1.4-kilobase insert complementary to at least part of the adenosine deaminase mRNA. Using this cDNA as a specific hybridization probe, all deoxycoformycin-resistant variants were shown to have increased amounts of adenosine deaminase mRNA and gene sequences. The relative increase in the level of mRNA and gene copy number was similar to the relative increase in enzyme activity for most resistant cell lines. However, the degree of adenosine deaminase gene amplification in one deoxycoformycin-resistant cell line (6-10-200) was 3-4-fold less than the relative increase in adenosine deaminase mRNA. These results indicate that the increased adenosine deaminase activity in deoxycoformycin-resistant rat hepatoma cells is due in large part, but not exclusively, to gene amplification.
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PMID:Amplification of adenosine deaminase gene sequences in deoxycoformycin-resistant rat hepatoma cells. 660 47

Pentostatin (I), a tight-binding inhibitor of adenosine deaminase, was evaluated in combination with the partially effective antitumor nucleoside N6-(delta 2-isopentenyl)adenosine (II) for cytotoxic activity against cultured L-1210 lymphocytic mouse leukemia cells. Although I alone (less than or equal to 10 micrograms/ml) was ineffective, it significantly potentiated and prolonged the cytotoxic and cytostatic activities of II. The combination of I (2-10 micrograms/ml) with II (25 micrograms/ml) resulted in inhibition of cellular proliferation (80-96%) within 24 hr with maintenance at that level for an extended period of time due to the continued ability of I to prevent the facile deamination of the allylic side chain of II. This type of adjuvant chemoprotection has potential use for other labile oncologic agents.
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PMID:Increased cytotoxicity of N6-(delta 2-isopentenyl)adenosine in combination with pentostatin against L-1210 leukemia cells. 660 32

The effects of adenosine (12.5 nmol/rat, i.c.v.) and 2'-deoxycoformycin (2.0 mumol/kg, i.p.) on sleep and wakefulness were examined in rats. Adenosine significantly decreased wakefulness and increased both deep slow-wave sleep and total sleep. 2'-Deoxycoformycin, a potent inhibitor of adenosine deaminase, was administered at a dose which did not produce significant sedative and hypnotic effects, when given alone (although a 4-fold greater dose of this drug has been shown to be hypnogenic in rats) in order to examine the possible potentiation of exogenously administered adenosine. No such potentiation was observed, since treatment with both drugs produced effects qualitatively similar, although not statistically significant, to those of adenosine alone. These data clearly indicate that adenosine is a hypnogenic substance in rats and suggest that these effects may involve adenosinergic receptor-mediated modulation of the activity of central adenylate cyclase.
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PMID:The effects of adenosine and 2'-deoxycoformycin on sleep and wakefulness in rats. 660 25

An analytical method for determination of 2'-deoxycoformycin (2'-DCF) concentrations in plasma and urine was developed based upon a modification of adenosine deaminase (ADA) inhibition assays described in the literature. The method involves the spectrophotometric monitoring of the rate of deamination of adenosine by the enzyme in the presence of various concentrations of the inhibitor 2'-DCF, and relating the deamination rate to the 2'-DCF concentration. In the course of developing the method, it was found that adenosine deaminase appears to lose activity after dilution with phosphate buffer (pH 7.2). Enzyme inactivation was found to occur mono-exponentially with time and, in order to accommodate for this inactivation, a method was developed for quantitating 2'-DCF which takes into consideration the relative activity of the enzyme in the incubation mixtures. The results obtained from the analysis of samples containing known concentrations of 2'-DCF were fitted to a three-dimensional standard surface by means of a nonlinear least-squares regression computer program. Quantitation of 2'-DCF in patient samples is accomplished by an ADA inhibition titration technique in which the spectrophotometrically determined absorbance change is related to the two independent variables, the concentration of 2'-DCF in the standards and the relative time of the analysis. As little as 1 ng/ml of 2'-DCF in plasma can be quantitated with the assay.
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PMID:An enzymatic kinetic method for the determination of 2'-deoxycoformycin in biological fluids. 661 Apr 19


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