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)

In conventional clinical use, cytosine arabinoside (ara-C) is rapidly deaminated by pyrimidine nucleoside deaminase to the nontoxic compound uracil arabinoside. Tetrahydrouridine (THU) effectively inhibits this enzymatic degradation but is by itself nontoxic. This study demonstrates that concomitant administration of THU markedly increases the myelosuppressive potency of ara-C. When 25 or 50 mg/kg of THU iv and 0.1--0.2 mg/kg of ara-C iv are given daily x 5 days, they produce moderate-to-severe leukopenia and mild-to-moderate thrombocytopenia. A dose of 25 mg/kg of THU with 0.1 mg/kg of ara-C iv daily x 5 days appears appropriate for phase II studies; it produces myelosuppression equivalent to that produced by 3 mg/kg/day x 5 days of ara-C alone. No toxicity occurred with this combination that would not have been expected from ara-C given alone in an equitoxic dose. Although THU and ara-C produced a reduction in peripheral blood and bone marrow blast cells in eight of nine patients with acute leukemia, bone marrow remission did not occur in any of these heavily pretreated patients.
 ...
PMID:Phase I evaluation of tetrahydrouridine combined with cytosine arabinoside. 38 91

The interaction between 2'-deoxycytidine (dCyd) and 1-beta-D-arabinofuranosylcytosine (ara-C), administered at pharmacologically achievable concentrations, was examined in four continuously cultured human leukemia cell lines, HL-60, KG-1, K-562, and CCRF-CEM. In three of the cell lines (HL-60, K-562, and CCRF-CEM), co-administration of 20 or 50 microM dCyd with 10 microM ara-C reduced ara-CTP formation by at least 90% and incorporation of ara-C into DNA by at least 80%. In contrast, KG-1 cells exhibited substantially smaller reductions in both ara-CTP formation and incorporation of ara-C into DNA under identical conditions. KG-1 cells were distinguished by the highest activity of the enzyme cytidine deaminase of the four lines assayed, and exhibited the smallest increments in the intracellular accumulation of both dCyd and deoxycytidine triphosphate (dCTP) in response to exogenous dCyd. Co-administration of 1 mM tetrahydrouridine (THU) or 0.5 mM deoxy-tetrahydrouridine (dTHU) had little effect on the ability of dCyd to antagonize ara-C metabolism in HL-60, KG-1 and K-562 cells. In contrast, these deaminase inhibitors substantially increased the intracellular accumulation of dCTP as well as the ability of dCyd to antagonize ara-CTP formation and incorporation of ara-C into DNA in KG-1 cells. THU and dTHU also permitted dCyd to antagonize ara-C growth inhibitory effects in KG-1 cells to the extent observed in the other leukemic cell lines. These studies suggest that the intracellular deamination of exogenous deoxycytidine may influence the degree to which this nucleoside antagonizes ara-C metabolism and toxicity in some leukemic cells. They also raise the possibility that deaminase inhibitors may be employed to modulate, and perhaps to improve, the therapeutic selectivity of pharmacologically relevant concentrations of ara-C and dCyd in the treatment of acute leukemia in man.
 ...
PMID:Effect of tetrahydrouridine and deoxytetrahydrouridine on the interaction between 2'-deoxycytidine and 1-beta-D-arabinofuranosylcytosine in human leukemia cells. 203 Jun 1

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.
 ...
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.
 ...
PMID:Pharmacokinetics of N4-behenoyl-1-beta-D-arabinofuranosylcytosine in patients with acute leukemia. 685 Jun 47

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.
 ...
PMID:Intracellular pharmacodynamics of ara-C and flowcytometric analysis of cell cycle progression in leukemia chemotherapy. 920 53

This note highlights our understanding and thinking about the feasibility of l-asparaginase as therapeutics for multiple diseases. l-asparaginase enzyme (l-asparagine amidohydrolase, EC 3.5.1.1) is prominently known for its chemotherapeutic application. It is primarily used in the treatment of acute lymphoblastic leukemia in children. It is also used in the treatment of other forms of cancer Hodgkin disease, lymphosarcoma, acute myelomonocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, reticulosarcoma and melanosarcoma (Lopes et al. Crit Rev Biotechnol 23:1-18, 2015). It deaminates l-asparagine present in the plasma pool causing the demise of tumor cell due to nutritional starvation. The anti-tumorigenic property of this enzyme has been exploited for over four decades and evidenced as a boon for the cancer patients. Presently, the medical application of l-asparaginase is limited only in curing various forms of cancer.
 ...
PMID:l-Asparaginase: a feasible therapeutic molecule for multiple diseases. 2987 9