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)

The antiproliferative activity of 9-beta-D-arabinofuranosyladenine 5'-monophosphate against a cultured line of mouse leukemia cells (L1210/C2) was enhanced by addition of either 2'-deoxycoformycin or erythro-9-(2-hydroxy-3-nonyl)adenine. The activity of 9-beta-D-arabinofuranosyladenine 5'-monophosphate, alone or in combination with either of the two inhibitors of adenosine deaminase, was comparable to that of 9-beta-D-arabinofuranosyladenine (ara-A), apparently reflecting the rapid conversion of 9-beta-D-arabinofuranosyladenine 5'-monophosphate to ara-A by L1210/C2 cells. Several ara-A analogs were assayed for antiproliferative activity against L1210/C2 cells; of these, only 9-beta-D-arabinofuranosyladenine 5'-O-methylphosphate and 2'-deoxy-2'-amino-9-beta-D-arabinofuraosyladenine were active. Addition of 2'-deoxycoformycin to cell culture fluids enhanced the activity of 9-beta-D-arabinofuranosyladenine 5'-O-methylphosphate suggesting conversion to an adenosine deaminase-sensitive intermediate, presumably ara-A.
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PMID:Antiproliferative effects of 9-beta-D-arabinofuranosyladenine 5'-monophosphate and related compounds in combination with adenosine deaminase inhibitors against mouse leukemia L1210/C2 cells in culture. 8 84

A unique seven-membered heterocyclic-ring inhibitor of adenosine deaminase was studied. One preparation of the compound inhibited replication of herpes simplex virus in the absence of adenine arabinoside. In this capacity, the minimal inhibitory concentration of deaminase inhibitor for herpes simplex virus type 1 (HSV-1), with 50 percent reduction of plaque-forming units as the end point, was 37.7 mug/ml. This activity compared favorably with the inhibitory activity of ara-hypoxanthine (34.1 mug/ml). Another preparation of deaminase inhibitor lacked antiviral activity. On the other hand, the adenosine deaminase inhibitor was active at a concentration of 0.009 mug/ml as a potentiator of the inhibition of HSV-1 by adenine arabinoside. The potentiation of adenine arabinoside by deaminase inhibitor is about 4,000 times more potent than the activity of the direct inhibitory effect on HSV-1. The nature of the possible contaminant of the preparation in question is unknown. Coformycin, another inhibitor of adenosine deaminase, had no antiviral activity in the absence of adenine arabinoside.
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PMID:Antiviral activity of an adenosine deaminase inhibitor: decreased replication of herpes simplex virus. 16 17

The antiviral activity of the fraudulent nucleoside arabinosyladenine (ara-A) against herpes simplex virus (HSV) type 1 was increased nearly 20-fold by the adenosine deaminase inhibitor, coformycin. The combination of ara-A plus coformycin was 90 times more potent in blocking HSV replication than was arabinosylhypoxanthine (ara-H). In suspension culture both drugs were more active than they were in monolayer culture. Deoxyribonucleic acid (DNA) synthesis also was inhibited by the nucleosides. Depending upon the species of DNA examined, ara-A was 8 to 15 times more active in the presence of coformycin, and the combination was 35 to 70 times more potent than ara-H. Both drugs inhibited total DNA synthesis to the same extent in uninfected and HSV-infected KB cells. In contrast, viral DNA synthesis was three to six times more susceptible to inhibition than was cellular DNA synthesis. Inhibition of viral DNA synthesis was more pronounced in suspension culture than in monolayer culture. However, the method of cell propagation did not alter the degree to which the drugs inhibited DNA synthesis in uninfected KB cells. An index has been derived to quantitate the extent of the selective inhibition of viral or cellular DNA synthesis. Fifty percent inhibitory concentrations of a drug were calculated for uninfected KB DNA synthesis and viral DNA synthesis and expressed as a ratio. The logarithm of this ratio was termed the selective index and was positive if viral DNA synthesis was inhibited preferentially or negative if uninfected KB DNA synthesis was more strongly inhibited. Data from experiments performed in monolayer culture gave positive selective index values of 0.3, 0.5, and 0.4 for ara-A plus coformycin, ara-A, and ara-H, respectively. Values of 0.7 and 0.6 were obtained from suspension culture data for ara-A plus coformycin and ara-H, respectively. Considered collectively, the data presented in this communication establish that coformycin increased the potency of ara-A but did not increase its selectivity.
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PMID:Antiviral activity of arabinosyladenine and arabinosylhypoxanthine in herpes simplex virus-infected KB cells: selective inhibition of viral deoxyribonucleic acid synthesis in the presence of an adenosine deaminase inhibitor. 18 47

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 multiple microtrephination technique was used in the rabbit cornea to compare the activity against herpes simplex virus (hsv) of adenine arabinoside (ara-A), ara-A 5'monophosphate (ara-AMP) and hypoxanthine arabinoside (ara-Hx), and to determine the effect of addition of adenosine deaminase inhibitor (ADAI) to each. The greatest antiviral activity was shown by ara-AMP, and the least by ara-Hx. ADAI increased the activity of ara-A but had no effect on ara-AMP or ara-Hx.
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PMID:Antiviral activity in the rabbit cornea of adenine arabinoside, Ara-A 5' monophosphate, and hypoxanthine arabinoside; and interactions with adenosine deaminase inhibitor. 19 39

Deoxyadenosine but not adenosine reversed the antiviral activity of 9-beta-D-arabinofuranosyladenine (ara-A) and 9-beta-D-arabinofuranosylhypoxanthine (ara-H) when used in the presence of coformycin, an inhibitor of adenosine deaminase. In suspension cultures of KB cells, 10 muM ara-A inhibited the replication of herpes simplex virus type 1 by 80%. Concomitant addition of 50 muM deoxyadenosine reduced the antiviral activity of 10 muM ara-A to only 40% inhibition. Adenosine failed to antagonize the antiviral activity. In monolayer cultures of KB cells, the 50% inhibitory concentration of ara-A was increased from 1.5 to 2.9 muM by 2 muM deoxyadenosine and to 8.5 muM by 10 muM deoxyadenosine. Analysis of the dose-response data by a double reciprocal plot method indicated that the antagonism was competitive. The antiviral activity of ara-H also was antagonized by deoxyadenosine. The 50% inhibitory concentration of ara-H was increased from 42 muM to 70, 91, or 121 muM by the concurrent addition of 5, 10, or 20 muM deoxyadenosine. Competitive antagonism could not be demonstrated. In the absence of the adenosine deaminase inhibitor, neither ara-A nor ara-H was antagonized by deoxyadenosine. Since such inhibitors were not available unitl recently, previous investigators were unable to observe the antagonistic capacity of deoxyadenosine.
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PMID:Deoxyadenosine antagonism of the antiviral activity of 9-beta-D-arabinofuranosyladenine and 9-beta-D-arabinofuranosylhypoxanthine. 20 16

A cell culture system has been utilized to measure the effects of drugs on DNA synthesis in uninfected and HSV-(herpes simplex virus)-infected KB cells. DNA from HSV-infected cells was separated into viral and cellular components by isopycnic centrifugation in CsCl gradients. The amount of [3H]thymidine incorporated into acid-insoluble material was measured in the absence and presence of drugs. Dose-response relationships were established by linearly regressing the probit value of the percent inhibition DNA synthesis against the logarithm of drug concentration. Fifty percent inhibitory (I50) concentrations were interpolated from the corresponding regression lines for inhibition of the following: (i) DNA synthesis is uninfected KB cells, (ii) total DNA synthesis in HSV-infected KB cells (iii) cellular DNA synthesis in HSV-infected cells, and (iv) viral DNA synthesis in HSV-infected cells. We have derived an index (SI, selective index) that quantifies the preferential inhibition of viral or uninfected cellular DNA synthesis. This index can be expressed as SI = log10 I50 concentration for DNA synthesis in uninfected cells divided by I50 concentration for viral DNA synthesis in HSV-infected cells. The SI is positive if viral DNA synthesis is inhibited preferentially and negative if uninfected cellular DNA synthesis is more strongly inhibited. A positive SI value of 0.5 was obtained for the clinically useful antiviral drug arabinosyladenine (ara-A) and a value of 0.4 for its metabolite, arabinosylhypoxanthine (ara-H). Although the adenosine deaminase inhibitor coformycin greatly increased the potency of ara-A, the inhibitor did not increase the selectivity of the drug (SI = 0.3). Stallimycin (distimycin A) (SI = 0.3) and phosphonoacetic acid (SI = 0.3) were similarly effective in preferentially inhibiting the synthesis of HSV DNA. In contrast, arabinosylcytosine (ara-C) and ribavirin inhibited DNA synthesis in uninfected cells to a greater degree than viral DNA synthesis (SI = -0.5 and -1.9, respectively). An analysis of the advantages and limitations of this experimental procedure is made and the suggestion is offered that the in vitro determination of a drug's selective index may be a valid predictor of clinical usefulness.
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PMID:The selective inhibition of viral DNA synthesis by chemotherapeutic agents: an indicator of clinical usefulness? 21 84

The minimum inhibitory concentration (MIC) of adenine arabinoside (ara-A) in rabbit kidney microtiter tissue cultures (RK-13) to a prototype strain of herpes simplex virus, type 1 (E115) based upon inhibition of cytopathic effects is 1.5 mug/ml. In this system, the MIC of arabinosylhypoxanthine (ara-Hx), the major in vivo metabolic derivative of ara-A, is 75 mug/ml. Inhibition of cytopathic effects of herpes simplex virus, type 1 (HSV-1) in microtiter wells of RK-13 cells varies directly with the concentrations of ara-A or ara-Hx, and inversely with residual HSV-1. The MIC of ara-A for HSV-1 in RK-13 cells is 5-20 times lower than similar measures with vero renal, mouse embryo, or human foreskin cultures. With RK-13 tissue cultures in microtiter plates, an assay for "ara-A equivalents" in human body fluids was developed which compares in sensitivity with high pressure liquid chromatography and has the advantage of simultaneously measuring combined antiherpesvirus effects of ara-A and its major metabolic derivative, ara-Hx. In vitro checkerboard studies in RK-13 cells confirmed that ara-A and ara-Hx in combination had antiviral effects which are synergistic. The total of the fractional MIC of ara-A plus ara-Hx in combination also varies inversely with residual HSV-1 in microtiter wells. Because virus adsorption is complete at 2 h before specimens to be tested are added in this assay, and because human interferon is not measured in rabbit cells, the antiviral assay is not affected by the presence of type-specific antiherpesvirus antibody or human interferon.Antiviral activity (AVA) was assayed as ara-A equivalents in sera and urines from 10 patients with serious herpesvirus infections who received 2.5-20 mg/kg daily of ara-A by intramuscular or intravenous routes. When a dosage schedule of 10 mg/kg per day or more was used, sustained concentrations of AVA that ranged from 0.8 to 14.4 mug/ml were found. When an inhibitor of adenosine deaminase (covidarabine) was not added to the specimens, mean serum concentrations were congruent with3.0 mug/ml (10 mg/kg per day, i.v.), and 4.1 mug/ml (20 mg/kg per day). However, in a single patient given 20 mg/kg of ara-A daily with covidarabine immediately added to the sera, the mean concentration of AVA was 12.9 mug/ml. Urines contained even higher AVA. Assays of 19 sera were performed both by microbiologic assay for AVA and by high pressure liquid chromatography for ara-A and ara-Hx. AVA was greater by microbiologic assay, and was greater than that which could be accounted for by stoichiometric chromatographic measures of ara-A and ara-Hx. These results with sera of treated patients are consistent both with the in vitro synergy of ara-A and ara-Hx found by checkerboard titrations, and with the beneficial responses to ara-A of patients with herpesvirus infections reported here and elsewhere.
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PMID:Antiherpesvirus activity in human sera and urines after administration of adenine arabinoside: in vitro and in vivo synergy of adenine arabinoside and arabinosylhypoxanthine in combination. 21 24

A limited number of biologically active materials were examined for their relative ability to selectively inhibit the replication of Gross or Rauscher murine leukemia virus (MLV) in Swiss mouse embryo cells by means of the UV-XC plaque-reduction assay. Among the compounds demonstrating significant antiviral activity against Gross MLV in vitro were 1-(4-fluorobenzyloxy) adenosine (FBAR), polyadenylic acid [poly(A)], the carbocyclic analogue of 6-methylthiopurine ribonucleoside (C-MeMPR), 3-(2,4-dinitrophenylhydrazonemethyl)rifamycin SV (AF/DNFI), and phosphonoacetic acid (PAA). Five compounds that exhibited significant antiviral activity against MLV in vitro were tested for similar activity against Rauscher MLV in vivo. Three of these selected compounds, pyrazofurin (pyrazomycin), ribavirin (Virazole), and 9-beta-D-arabinofuranosyladenine (ara-A), produced a significant (50%-100%) inhibition of virus-induced splenomegaly development in mice, whereas the other two candidate inhibitors, 3-deazauridine (deazaUR) and rifamycin SV, the other two candidate inhibitors, 3-deazauridine (deazaUR) and rifamycin SV, failed to demonstrate any in vivo activity in this 21-day leukemogenesis assay. The administration of an inhibitor of adenosine deaminase (Co-vidarabine) in combination with ara-A resulted in an enhanced antiviral response in both infected cell cultures and animals. Co-vidarabine also increased the potency of ara-AMP against Gross MLV in vitro, indicating the probable dephosphorylation of the compound to ara-A and its subsequent deamination to ara-H in this system.
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PMID:Selective inhibition of RNA tumor virus replication in vitro and evaluation of candidate antiviral agents in vivo. 28 Jan 46


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