Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.4 (deaminase)
 5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PLDR is one known cause of tumor cell radioresistance. Drugs like ara-A have been reported to inhibit PLDR, thus increasing antineoplastic effects. In this research, ara-A concentration was measured by high-pressure liquid chromatography (HPLC) to investigate its metabolism. Ara-A deaminases in vitro in about 30 minutes, but by using a deaminase inhibitor such as 2'-deoxycoformycin, a fixed level of ara-A can be maintained. Furthermore, the new derivative, ara-AMP, does not deaminase. It is hoped that antineoplastic effects can be effectively increased by maintaining the ara-A concentration through the combined use of deaminase inhibitors and through new derivatives.
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PMID:[Problems of antineoplastic effects by PLDR (potential lethal damage repair) inhibitor--pharmacokinetics]. 633 57

A subline of human KB cells that was resistant to 1-beta-D-arabinofuranosylcytosine (ara-C) was established by continuous exposure of the cells to increasing concentrations of ara-C. Thirteen resistant clones were isolated from the resistant subline (KB/ara-C). KB/ara-C showed 1,300-fold higher resistance than the parent KB cells to ara-C; the most resistant clones, clones 7 and 10, showed 1,330-fold higher resistance. In the absence of ara-C, the resistance of the parent KB/ara-C cells was stable for at least 14 weeks, whereas that of clone 7 was stable for 10 weeks, but was slightly less after 14 weeks. The ara-C kinase and ara-C deaminase activities of the 13 clones and the cellular uptake of ara-C by several clones were measured. In general the clones showed decreased deoxycytidine kinase activity and decreased cellular uptake of ara-C. Most clones had higher cytidine deaminase activity than KB cells, but some had activity similar to that of the KB cells. A clear inverse relationship was found between the ara-C sensitivity of the clones and their kinase activity, but not their deaminase activity or their ara-C uptake. These results clearly demonstrate that a major mechanism of ara-C resistance of these human KB cells was a decrease in the activity of the ara-C activating enzyme deoxycytidine kinase. The parent KB/ara-C cells showed no clear cross-resistance to various antitumor agents other than an ara-C derivative, including metabolic inhibitors, alkylating agents, DNA binders and mitotic spindle poisons.
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PMID:Establishment of human KB cells resistant to 1-beta-D-arabinofuranosylcytosine, and mechanisms of cellular resistance in isolated clones. 648 76

The pharmacokinetics of high-dose cytosine arabinoside (HiDAC) given as a three-hour intravenous infusion at 3 g/m2 were studied in five patients with acute leukemia during relapse and/or remission of their disease. Apparent steady state plasma levels of ara-C during 13 infusions averaged 115 +/- 32 microM. Upon cessation of the infusion, cytosine arabinoside (ara-C) was rapidly cleared from the plasma. The apparent postinfusion kinetics of ara-C were triexponential with a distribution half-life of 16 minutes and elimination half-lives of 1.8 hours and six hours. Total clearance averaged 86 L per hour and mean residence time averaged 0.47 hours. Disease status (relapse or remission) had no apparent effect on the pharmacokinetic characteristics of ara-C. Peak levels of ara-U averaged 310 microM and the metabolite had an average apparent elimination half-life of 3.75 hours. Despite the persistence of ara-U at about 100 microM at the time of administration of subsequent infusions of ara-C, there was no further accumulation of ara-U in the plasma with repetitive infusions of HiDAC. In vitro studies indicate that ara-U can exert an inhibitory effect on deoxycytidine (dCyd) deaminase activity. The ratio of the Ki of ara-U to the Km of ara-C for cytidine (Cyd)-dCyd deaminase is 40:1; however, during the gamma phase of ara-C elimination, the ratio of ara-U:ara-C in plasma is at least 100:1. Thus, a retardation of systemic catabolism of ara-C by ara-U is possible. Two to three hours after the termination of the HiDAC infusion, the ara-C cerebrospinal fluid: plasma ratio is 1-3:1, a feature of potential therapeutic significance. The slower elimination of ara-C from the CSF may also contribute to the plasma gamma half-life.
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PMID:Alteration of the pharmacokinetics of high-dose ara-C by its metabolite, high ara-U in patients with acute leukemia. 666 93

N4-Behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC), a lipophilic and deaminase-resistant derivative of 1-beta-D-arabinofuranosylcytosine (ara-C), was studied pharmacologically in patients with acute leukemia. The concentrations of BHAC, ara-C, and 1-beta-D-arabinofuranosyluracil were measured by high-performance liquid chromatography, bioassay, and gas chromatography-mass spectrometry-mass fragmentography, respectively. The data of plasma BHAC concentrations were analyzed by a MULTI computer program. In seven patients given BHAC (200 mg/body weight; 2.97 to 4.26 mg/kg) i.v. for 90 min, the plasma disappearance curve of BHAC was biphasic with a mean initial half-life of 0.37 hr and a mean second half-life of 5.27 hr. The apparent volume of the central compartment and the apparent volume of distribution were 0.047 and 0.316 liter/kg, respectively; the systemic clearance was 0.051 liter/hr/kg. BHAC concentrations in erythrocytes were significantly higher (p less than 0.01) than those in plasma at 4 to 22.5 hr after infusion, suggesting that the erythrocytes may act as a reservoir for the drug. The plasma 1-beta-D-arabinofuranosyluracil level increased to 603 ng/ml at 4 hr after infusion, and it was over 129 ng/ml for at least 22.5 hr after infusion. Plasma ara-C levels, which could be detected in only 2 of 11 patients examined, were maintained (over 0.08 micrograms/ml) for 8 hr after infusion. Urinary BHAC excretion was less than 0.2 micrograms/ml of the sensitivity limit in all samples. Prolonged urinary ara-C excretion was detected, but it was only 0.5% of the administered BHAC for 24 hr. At 12 hr after a 200-mg infusion of BHAC, BHAC level in bone marrow fluid was significantly higher (p less than 0.01) than that in plasma. In spite of the lipophilic nature of the agent, the BHAC concentration in cerebrospinal fluid was less than 0.2 micrograms/ml in 8 of 9 patients without meningeal involvement. These findings were thought to indicate a restricted and prolonged BHAC distribution including plasma, blood cells, and bone marrow fluids, which may be of importance in the administration of BHAC in the chemotherapy of hematological cancers.
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PMID:Pharmacokinetics of N4-behenoyl-1-beta-D-arabinofuranosylcytosine in patients with acute leukemia. 685 Jun 47

A novel metabolite was found in the urine and bile of mice given i.v. injections of N4-behenoyl-1-beta-D-arabinofuranosylcytosine (behenoyl-ara-C). Acid and alkaline hydrolysis of this metabolite resulted in the production of 1-beta-D-arabinofuranosylcytosine and succinic acid, as determined by thin-layer chromatography and high-performance liquid chromatography. Mass spectrometry identified this metabolite as N4-succinyl-1-beta-D-arabinofuranosylcytosine (succinyl-ara-C). This conclusion was supported by thin-layer chromatography and by the ultraviolet spectrum, upon which the characteristics of this metabolite agreed with those of succinyl-ara-C. Only a very small amount, if any, of this metabolite was found in the urine and bile of mice given injections of N4-stearoyl- or N4-palmitoyl-1-beta-D-arabinofuranosylcytosine, suggesting that behenoyl-ara-C was metabolized differently from the other two analogs. Comparison of the metabolites of behenoyl-ara-C, radiolabeled at different positions of the behenoyl-residue, suggested that behenoyl-ara-C was degraded by omega-oxidation and then by beta-oxidation, resulting in the production of succinyl-ara-C. This metabolite was more potent than behenoyl-ara-C in suppressing the in vitro proliferation of murine L1210 cells. The high therapeutic potency of behenoyl-ara-C in L1210-bearing mice may be ascribable to the contribution of succinyl-ara-C to the efficacy of behenoyl-ara-C, either by suppressing the proliferation of L1210 cells or by protecting 1-beta-D-arabinofuranosylcytosine, the possible eventual metabolite, from inactivation by deaminase.
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PMID:Production of N4-succinyl-1-beta-D-arabinofuranosylcytosine, a novel metabolite of N4-behenoyl-1-beta-D-arabinofuranosylcytosine, in mice and its biological significance. 723 44

The 2'-deoxy (2a) and 2'-ara-fluoro (3a) derivatives of zebularine [1-(beta-D-ribofuranosyl)-dihydropyrimidin-2-one, 1a] were phosphorylated in high yield to the 5'-nucleotides 2b and 3b, respectively, and characterized by HPLC, enzyme degradation, 1H, 13C and 31P NMR, and high resolution mass spectral analysis. Their inhibitory activity against partially purified MOLT-4 deoxycytidylate deaminase (dCMPD) in the presence of the allosteric effector deoxycytidine triphosphate (dCTP) and Mg+2 ion was examined. Compounds 2b and 3b inhibited dCMPD with Ki values of 2.1 x 10(-8) M and 1.2 x 10(-8) M, respectively. The parent nucleotide, zebularine monophosphate 1b was ineffective at concentrations > 100 mumol. The effect of the nucleosides, 1a-3a, as well as tetrahydrouridine (THU) and 2'-deoxy THU (dTHU), on the cellular production of DNA precursors was examined in human MOLT-4 peripheral lymphoblasts. It was shown that 1a, 2a and 3a all elevated intracellular dCTP and TTP levels in whole cells with the most powerful effect elicited by 1a. The 2'-fluoro derivative 3a was chemically phosphorylated much more cleanly and higher yield than 2a, without the formation of diphosphorylated by-products. This compound was found to be infinitely less sensitive to acid-catalyzed degradation than 2a. Since the substitution of fluorine for hydrogen had a slight potentiating effect on the dCMPD inhibitory activity while stabilizing the compound toward acid-catalyzed and enzymatic depyrimidination, compound 3b emerges as a very attractive tool for the pharmacological modulation of pyrimidine deaminase activity.
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PMID:Improved synthesis of zebularine [1-(beta-D-ribofuranosyl)-dihydropyrimidin-2-one] nucleotides as inhibitors of human deoxycytidylate deaminase. 858 52

Mammalian brain as well as mouse neuroblastoma (N18TG2) and rat basophilic leukaemia (RBL) cells were previously shown to contain "anandamide amidohydrolase', a membrane-bound enzyme sensitive to serine and cysteine protease inhibitors and catalyzing the hydrolysis of the endogenous cannabimimetic metabolite, anandamide (arachidonoyl-ethanolamide). With the aim of developing novel inhibitors of this enzyme, we synthesized three arachidonic acid (AA) analogues, i.e. arachidonoyl-diazo-methyl-ketone (ADMK), ara-chidonoyl-chloro-methyl-ketone (ACMK) and O-acetyl-arachidonoyl-hydroxamate (AcAHA), by adding to the fatty acid moiety three functional groups previously used to synthesize irreversible inhibitors of serine and cysteine proteases. The three compounds were purified and characterized by proton nuclear magnetic resonance and electron impact mass spectrometry. Their effect was tested on anandamide amidohydrolase partially purified from N18TG2 and RBL-1 cells and porcine brain. Pre-treatment of the enzyme with each compound produced a significant inhibition, with ADMK being the most potent (IC50 = 3, 2 and 6 microM) and AcAHA the weakest (IC50 = 34, 15 and 25 microM) inhibitors. The inactivated enzyme regained its full activity when chromatographed by anion-exchange chromatography, suggesting that none of the compounds inhibited the amidohydrolase in a covalent manner. Accordingly, Lineweaver-Burk profiles showed competitive inhibition by each compound. Conversely, the irreversible inhibitor of cytosolic phospholipase As, methyl-arachidonoyl-fluoro-phosphonate (MAFP), covalently inhibited the amidohydrolase. MAFP was active at concentrations 10(3) times lower than those reported for phospholipase A2 inhibition, and is the most potent anandamide amidohydrolase inhibitor so far described (IC50 = 1-3 nM). MAFP, ADMK and ACMK, probably by inhibiting anandamide degradation, produced an apparent increase of the in vitro formation of anandamide from its biosynthetic precursor N-arachidonoyl-phosphatidyl-ethanolamine.
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PMID:Novel inhibitors of brain, neuronal, and basophilic anandamide amidohydrolase. 907 Feb 24

To establish the most effective and reasonable mode of combining and administrering ara-C with other antileukemic agents in chemotherapy for acute leukemia, the action mechanisms of ara-C was investigated in terms of intracellular pharmacodynamics and the biochemical action mechanism of ara-C was investigated in leukemic cell. Rensonable methods of administering the agent was considered as follows. 1. A low level of ara-C in the incubation medium induced a higher concentration of ara-CTP in leukemic cells. Therefore, maintenance of even a low plasma ara-C level after ara-C therapy could enhance the antileukemic effect of the agent. 2. Ara-C activation was increased in the presence of 6MP by suppressing elevation of deaminase activity in the cell suspection medium. Therefore, administration of 6MP prior to ara-C therapy could enhance the antileukemic effect of the agent. 3. Ten micrograms/ml of ara-C, corresponding to intermediate dose ara-C therapy, induced rapid endonuclease activation, DNA ladder fragmentation and subsequent apoptosis in large numbers of leukemic cells, suggesting that intermediate dose ara-C therapy is effective in reducing residual leukemic cells after therapy. 4. Blood transfusion for patients with high grade anemia prior to bebenoyl ara-C therapy prolonged higher and longer plasma drug maintenance. 5. Flowcytometry of cell cycle progression of L1210 cells treated by ara-C and daunorubicin revealed that a combination of ara-C first and daunorubicin second was superior to the reverse sequential combination. These improvements in the mode of administering ara-C could provide better results following chemotherapy for leukemia.
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PMID:Intracellular pharmacodynamics of ara-C and flowcytometric analysis of cell cycle progression in leukemia chemotherapy. 920 53

1-beta-D-Arabinofuranosylcytosine (ara-C) is used empirically at a low, conventional, or high dose. Ara-C therapy may be optimal if it is directed by the clinical pharmacokinetics of the intracellular active metabolite of ara-C, 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP). However, ara-CTP has seldom been monitored during low- and conventional-dose ara-C therapies because detection methods were insufficiently sensitive. Here, with the use of our newly established method (Cancer Res., 56, 1800 -- 1804 (1996)), ara-CTP was monitored in leukemic cells from acute myelogenous leukemia patients receiving low- or conventional-dose ara-C [subcutaneous ara-C administration (10 mg / m(2) ) (3 patients), continuous ara-C infusion (20 or 70 mg / m(2) / 24 h) (7 patients), 2-h ara-C infusion (70 mg / m(2) ) (4 patients), and 2-h infusion of N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine, a deaminase-resistant ara-C derivative (70 mg / m(2) ) (6 patients)]. Ara-CTP could be determined at levels under 1 microM. There was a close correlation between the elimination half-life values of the plasma ara-C and the intracellular ara-CTP. The presence of ara-C in the plasma was important to maintain ara-CTP. The continuous ara-C and the 2-h N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine infusions maintained ara-CTP and the plasma ara-C longer than the subcutaneous ara-C or the 2-h ara-C infusion. They also afforded relatively higher ara-CTP concentrations, and consequently produced ara-CTP more efficiently than the 2-h ara-C infusion. Different administration methods produced different quantities of ara-CTP even at the same dose.
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PMID:Monitoring of intracellular 1-beta-D-arabinofuranosylcytosine 5'-triphosphate in 1-beta-D-arabinofuranosylcytosine therapy at low and conventional doses. 1137 64


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