Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1-beta-d-Arabinofuranosylcytosine (ara-C), an effective drug for acute leukemias, must be phosphorylated to its 5'-triphosphate, ara-CTP, for activity. Our previous studies during therapy of acute myelogenous leukemia (AML) patients demonstrated that the accumulation of ara-CTP in circulating leukemia blasts was increased by a median of 2-fold when fludarabine (30 mg/m2/day over 30 min) was infused 4 h prior to intermediate dose ara-C. The augmentation was dependent on the cellular concentration of fludarabine triphosphate (F-ara-ATP). To determine the lowest dose of fludarabine needed for modulation of ara-C metabolism, the present study administered fludarabine at a test dose (15 mg/m2 over 30 min) followed by 2 g/m2 ara-C infused over 4 h. The next day, the fludarabine/ara-C couplet was repeated but with a standard dose (30 mg/m2) of fludarabine. There was a dose-dependent accumulation of F-ara-ATP in circulating leukemia blasts; the median peak concentrations were 33 and 41 microM with 15 and 30 mg/m2 of fludarabine, respectively. These intracellular levels of F-ara-ATP effectively increased ara-CTP accumulation to similar levels. To further titrate the dose of fludarabine, the next cohort of patients (n = 4) initially received fludarabine test doses of 7.5 or 5 mg/m2, followed by the 30 mg/m2 dose of fludarabine on the next day; each dose was infused 4 h prior to 2 g/m2 of ara-C. The peak levels of F-ara-ATP at 7.5 and 5 mg/m2 fludarabine were between 3 and 39 microM. The AML blasts that achieved >/=10 microM intracellular F-ara-ATP accumulated ara-CTP similar to the levels achieved after 30 mg/m2 of fludarabine. However, <10 microM intracellular F-ara-ATP resulted in less ara-CTP accumulation compared to that observed after the conventional dose of fludarabine. These data suggest that the modulation of the ara-CTP accumulation by fludarabine is dependent on the cellular concentration of F-ara-ATP, and that 15 mg/m2 fludarabine infused over 30 min consistently produces cellular F-ara-ATP levels that maximize ara-CTP accumulation in AML blasts. These findings point to the feasibility of intensifying the fludarabine-ara-C regimen by using fludarabine as a 15 mg/m2/dose twice daily with intermediate-dose ara-C.
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PMID:Minimum dose of fludarabine for the maximal modulation of 1-beta-D-arabinofuranosylcytosine triphosphate in human leukemia blasts during therapy. 981 41

Previous in vitro investigations demonstrated that human leukemia cells, when incubated with hematopoietic growth factors such as granulocyte-colony-stimulating factor (G-CSF), augment the accumulation of the triphosphate 1-beta-D-arabinofuranosylcytosine (ara-C cytarabine). To test whether G-CSF infusion prior to ara-C infusion would biologically modulate the accumulation of ara-9-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) and other ara nucleotides in the leukemia blasts during therapy, protocols were designed to infuse G-CSF prior to fludarabine (9-beta-D-arabinofuranosyl-2-fluoroadenine monophosphate) and ara-C to increase the accumulation of the active triphosphates [9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-triphosphate (F-ara-ATP) and ara-CTP] in acute myelogenous leukemia (AML) blasts during therapy. To complement these in vivo studies, ex vivo accumulation of ara-CTP was also investigated before and after G-CSF infusion. Patients (n = 5) treated on the fludarabine/ara-C/G-CSF regimen received a 30 mg/m2 dose of fludarabine followed by a 2 g/m2 dose of ara-C infused i.v. for 4 h. Beginning at 24 h, and every day, patients received a 6-h infusion of 400 microgram/m2 G-CSF. At 48 h, the fludarabine and ara-C couplet was repeated. Comparison of F-ara-ATP pharmacokinetics in circulating AML cells of patients on the fludarabine/ara- C/G-CSF regimen demonstrated that the area under concentration time curve (AUC) of F-ara-ATP increased significantly (median, 1.4-fold; range, 0.9-1.5; P = 0.045) after G-CSF infusion. This was due to an increased rate of F-ara-ATP accumulation by AML cells. The AUC of ara-CTP, on the other hand, was not affected (median, 1.0-fold; range, 1.0-1.2; P = 0.571) after G-CSF infusion. Because fludarabine potentiates the accumulation of ara-CTP, the effect of G-CSF on ara-CTP metabolism may not be evident in the AML blasts of patients on the fludarabine/ara-C/G-CSF regimen. To determine the effect of G-CSF when ara-C was infused alone, four additional patients were treated on a pilot protocol in which ara-C (2 g/m2) was infused on days 1 and 3 and G-CSF on day 2. The AUC of ara-CTP accumulation in these patients decreased by a median of 48% after G-CSF infusion. Consistent with these in vivo investigations, ex vivo ara-CTP accumulation was decreased in the AML blasts after G-CSF infusion. Based on these data it could be concluded that (a) infusion of G-CSF before fludarabine augmented the rate of F-ara-ATP synthesis in circulating AML blasts during therapy, suggesting that G-CSF may benefit fludarabine therapy by biological modulation; (b) G-CSF did not increase ara-CTP accumulation, rather it may have caused it to decrease; and (c) these data imply that when G-CSF and ara-C are used in combination, administration of fludarabine prior to ara-C may maintain the ara-CTP AUC.
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PMID:Modulation of the cellular metabolism of cytarabine and fludarabine by granulocyte-colony-stimulating factor during therapy of acute myelogenous leukemia. 981 70

Arabinosylcytosine (ara-C) is a cytotoxic agent with major activity against acute leukemias. To exert this effect, it must first be phosphorylated to its active 5'-triphosphate, ara-CTP, which is incorporated into DNA. Our previous studies demonstrated that preincubation with arabinosyl-2-fluoroadenine (F-ara-A) increased the rate of ara-CTP accumulation in leukemia cells when incubated with 10 microM ara-C. Such concentrations of ara-C are readily obtained during intermittent bolus infusions of ara-C, and clinical trials were conducted using fludarabine in combination with 2-h infusions of intermediate-dose ara-C. During continuous infusion of ara-C, however, serum ara-C levels are <10 microM. Because the effectiveness of ara-C depends on the levels of intracellular ara-CTP and its incorporation into DNA, we sought to investigate the influence of fludarabine on pharmacodynamics of ara-C at concentrations of ara-C achieved during continuous infusion. Using the K562 human leukemic cell line, we established that incubation with 30 microM F-ara-A was able to modulate intracellular dNTP pools and achieve maximum enhancement of ara-CTP levels at all concentrations of ara-C tested (0.3-10.0 microM). The relative enhancement of ara-CTP concentrations ranged from 2.2- to 2.8-fold. Combination of F-ara-A with 1.0 and 3.0 microM ara-C also increased the incorporation of ara-CTP into DNA. To model the influence of F-ara-A on continuous infusion ara-C, cells were incubated with 1 microM ara-C alone or in combination with F-ara-A. The F-ara-A-incubated cells accumulated effective intracellular concentrations of F-ara-ATP, which resulted in greatly increased intracellular ara-CTP levels. These studies demonstrate the capacity of clinically attainable concentrations of F-ara-ATP to enhance the formation of ara-CTP at concentrations of ara-C that are achieved during a continuous infusion schedule. Given the important role intracellular ara-CTP concentrations and ara-CMP incorporation into DNA have on the ultimate cytotoxic capacity of ara-C against acute myelogenous leukemia blasts, these studies suggest a promising pharmacological model for improving the efficacy of the continuous infusion ara-C regimen.
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PMID:Influence of fludarabine on pharmacokinetics and pharmacodynamics of cytarabine: implications for a continuous infusion schedule. 981 15

Different metabolites of cytosine arabinoside (AraC) contribute to its cytotoxicity including incorporation of AraCTP into DNA, the incorporation of AraUMP into RNA, inhibition of polymerase alpha and beta (AraCMP/CTP), an impairment of repair mechanisms (AraCTP), alterations of phospholipid metabolism (AraCDP-choline), a direct membrane interaction (AraC), the alteration of signal transduction pathways (AraCDP-choline, AraCTP) and the induction of apoptosis. Since little is known about the potential differences in AraC metabolism between leukaemic blasts and normal haemopoietic progenitor cells, the formation of all known AraC metabolites was determined in bone marrow samples from patients with acute myeloid leukaemia (AML), healthy volunteers and specimens of cellsorted CD34+ haemopoietic stem cells. Highly significant differences were found for phosphorylated AraC metabolites (AraCMP, -CDP, -CTP, AraUMP) between AML and normal mononuclear bone marrow (ng/107 cells respectively 1.30 v 2.66; 2.65 v 7.50; 33.68 v 99.0; 1.18 v 5.70). The highest differences were found for formation of AraCDP-choline (3.75 v 12.86) which might be relevant for the high efficacy of high-dose AraC regimens. In contrast, no differences were found in the deamination product AraU (2.01 v 2.91). Only minute amounts of phosphorylated AraU derivatives were detected, providing an explanation for the lacking contribution of AraU to cytosine arabinoside cytotoxicity. Results in normal CD34+ haemopoietic stem cells did not differ significantly from normal bone marrow mononuclear cells and therefore justify their use as a surrogate in determining AraC-induced haematotoxicity. These data suggest a metabolic basis for the relative selectivity of AraC cytotoxicity for AML blasts and provide a means to determine the role of different metabolites and their related mechanism of action for overall AraC cytotoxicity.
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PMID:Leukaemic blasts differ from normal bone marrow mononuclear cells and CD34+ haemopoietic stem cells in their metabolism of cytosine arabinoside. 1023 9

The rate of ara-cytosine triphosphate (ara-CTP) accumulation and its retention has been correlated with 1-beta-D-arabinofuranosylcytosine (ara-C)-mediated toxicity and clinical outcome in childhood and adult leukemia. We tested to what extent preincubation with the ribonucleotide reductase inhibitors fludarabine (F-ara-A) and hydroxyurea (HU) enhanced ara-CTP levels in two human myeloid (HL-60, CMK) and two lymphoblastic leukemia cell lines (MOLT-4, BLIN-1) and also in blasts from 28 children with acute leukemia (AML: 14, ALL: 14). Incubation experiments carried out with cell lines showed F-ara-A and HU to be equipotent in increasing ara-CTP levels. The highest increase was observed in HL-60 cells whereas preincubation had no modulatory effect in MOLT-4 cells. Accordingly, modulation of intracellular ara-CTP levels differed between the subtypes of childhood acute leukemia: whereas in T-ALL (five) preincubation with F-ara-A and HU had no effect on intracellular ara-C metabolism, increased ara-CTP levels were seen in some cases of pre-B-ALL (seven). In myelogenous blasts (12) clinically relevant enhancement of ara-C toxification was regularly obtained with both, F-ara-A (1.9-fold) and HU (1.5-fold). In conclusion, our data suggest that combinations of ara-C and ribonucleotide reductase inhibitors are apt to increase ara-CTP levels depending on the individual cell type and its sensitivity towards ara-C modulators.
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PMID:Modulation of ara-CTP levels by fludarabine and hydroxyurea in leukemic cells. 1124 2

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

Cytarabine (ara-C) requires activation into its triphosphorylated form, ara-CTP, to exert cytotoxic activity. Cytoplasmic 5'-nucleotidase (5NT) dephosphorylates ara-CMP, a key intermediate, preventing accumulation of ara-CTP and may reduce cellular sensitivity to the cytotoxic activity of ara-C. To determine whether the level of expression of 5NT is correlated with clinical outcome in patients with acute myeloid leukemia (AML) treated with ara-C, this study analyzed the levels of messenger RNA expression of high Km 5NT by real-time polymerase chain reaction at diagnosis in blast cells of 108 patients with AML. High Km 5NT was expressed at diagnosis in the blast cells of 54% of patients. In univariate analysis, (1) patients whose blast cells contained high levels (values greater than the median value for total population) of high Km 5NT at diagnosis had significantly shorter disease-free survival (DFS) than patients with low levels of high Km 5NT (11 months versus 17.5 months, P =.02) and (2) high levels of high Km 5NT also predicted significantly shorter overall survival (15.7 months versus 39 months, P = .01) in young patients (< or = 57 years; median value for the entire population). In a multivariate analysis taking into account age, karyotype risk, and other factors found to have prognostic significance in univariate analysis, (1) high Km 5NT expression was an independent prognostic factor for DFS and (2) high levels of high Km 5NT also predicted significantly shorter overall survival in young patients. These results demonstrate that the expression of high levels of high Km 5NT in blast cells is correlated with outcome in patients with AML.
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PMID:Expression of high Km 5'-nucleotidase in leukemic blasts is an independent prognostic factor in adults with acute myeloid leukemia. 1153 30

N(4)-Behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC), a prodrug of 1-beta-D-arabinofuranosylcytosine, is used effectively for the treatment of leukemia in Japan. BHAC therapy may be more effective if it is delivered in conjunction with monitoring of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP), the intracellular active metabolite of ara-C derived from BHAC. However, previous monitoring methods for ara-CTP were insufficiently sensitive. Here, using our new sensitive method, we evaluated the ara-CTP pharmacokinetics in relation to the therapeutic response in 11 acute myelogenous leukemia patients who received a 2-h infusion of BHAC (70 mg / m(2)) in combination remission induction therapy. ara-CTP could be monitored at levels under 1 mM. BHAC maintained effective levels of plasma ara-C and intracellular ara-CTP for a longer time, even compared with historical values of high-dose ara-C. The area under the concentration-time curve of ara-CTP was significantly greater in the patients with complete remission than in the patients without response. This greater amount of ara-CTP was attributed to the higher ara-CTP concentrations achieved in the responding patients. There was no apparent difference of plasma ara-C pharmacokinetics between the two groups. Thus, for the first time, the ara-CTP pharmacokinetics was evaluated in relation to the therapeutic effect of BHAC, and the importance of ara-CTP was proven. Administration of optimal BHAC therapy may require monitoring of the ara-CTP pharmacokinetics in each individual patient.
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PMID:Close correlation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate, an intracellular active metabolite, to the therapeutic efficacy of N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine therapy for acute myelogenous leukemia. 1157 66

Published randomized trials on different cytarabine doses for the treatment of acute myeloid leukemia (AML) provide evidence of a dose-response effect. However, high-dose cytarabine (HIDAC) regimens correlate with increased morbidity and toxicity related mortality. Typical HIDAC regimens deliver 6 g/m2/d in infusion rates of 500-3000 mg/m2/h. However, pharmacokinetic measurements indicate that intracellular Ara-CTP formation is saturated at lower infusion rates than used in HIDAC schedules, probably causing cytarabine accumulation in the plasma and increased toxicity. It was our objective to investigate in a prospective non-randomized phase I-II study feasibility and efficacy of intermediate doses of cytarabine delivered at the presumptive saturating moderate infusion rate (mir-IDAC), as induction therapy in order to optimize intensified treatment for acute myeloid leukemia. Forty previously untreated patients younger than 60 years of age with de novo AML received intermediate doses of cytarabine (2-4 g/m2/d) at moderate infusion rates (250-667 mg/m2/h) over 6 or 8 h. Cytarabine was applied on alternate days (day 1, 3, 5, 7) in combination with an anthracycline as induction and consolidation therapy. Thirty-two of the 40 patients (80%, 95%CI:64-91%) achieved CR after induction treatment. Treatment-related mortality during induction chemotherapy was 2.5%. No cerebellar toxicity was observed. After two to four mir-IDAC courses stem cell harvesting was successful in 71% of the patients eligible for high-dose chemotherapy. After three years 56% (95%CI:40-72%) of all patients are alive and 59% (95%CI:42-76%) of the patients who entered CR are free of leukemia. In conclusion, favorable long-term outcomes and moderate acute toxicities were observed in patients with de novo AML treated with IDAC schedules delivered at moderate infusion rates (mir-IDAC) starting as induction treatment. The data suggest that a randomized trial should now be undertaken to examine whether mir-IDAC has clinical advantages over HIDAC.
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PMID:Intermediate-dose cytarabine treatment delivered at moderate infusion rates for de novo acute myeloid leukemia-results of a phase I-II study. 1199 57

Factors that reduce the intracellular concentration of triphosphorylated cytarabine (ara-CTP), the active form of cytarabine (ara-C), may induce chemoresistance in acute myeloid leukaemia (AML) patients. These factors include reduced influx of ara-C by the hENT1 transporter, reduced phosphorylation by deoxycytidine kinase (dCK), and increased degradation by high Km cytoplasmic 5'-nucleotidase (5NT) and/or cytidine deaminase (CDD). Increased levels of DNA polymerase alpha (DNA POL) and reduced levels of topoisomerase I (TOPO I) and topoisomerase II (TOPO II) have also been detected in ara-C-resistant cell lines. To determine whether these factors are implicated in clinical ara-C resistance, we analysed the expression of these parameters at diagnosis, using reverse transcription polymerase chain reaction, in the blast cells of 123 AML patients treated with ara-C. At diagnosis, hENT1, dCK, CDD, 5NT, TOPO I, TOPO II, DNA POL and MDR1 were expressed in 83%, 22%, 7%, 37%, 59%, 37%, 39% and 16% of patients respectively. In univariate analysis, patients with expression of 5NT or DNA POL at diagnosis had significantly shorter disease-free survival (DFS). In multivariate analysis, DNA POL positivity and hENT1 deficiency were related to a shorter DFS. In univariate analysis, patients with 5NT-positive blasts had significantly shorter overall survival (OS). In multivariate analysis, shorter OS was related to DNA POL positivity. These results suggest that expression of DNA POL, 5NT and hENT1 at diagnosis may be resistance mechanisms to ara-C in AML patients.
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PMID:In vivo mechanisms of resistance to cytarabine in acute myeloid leukaemia. 1206 Jan 21


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