Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antitumor activity and toxicity of two new 1-beta-D-arabinofuranosyl-cytosine (ara-C) conjugates of cortisol and corticosterone linked through a phosphodiester bond between the 5' and 21 positions of the respective moieties (cortisol- and corticosterone-p-ara-C) were investigated in L1210 lymphoid leukemia cells in mice. They are highly active against both i.p.- and i.c.-implanted ara-C-sensitive lymphoid leukemia in mice, exceeding the activity produced by the parent drug, ara-C. For example, corticosterone-p-ara-C exhibited the respective ILS values of 306% at 50 mg/kg/day X 9 and 294% at 75 mg/kg/day X 9 on survivals of i.p.- and i.c.-inoculated L1210 leukemic mice. The effectiveness of the conjugates seems to depend on schedules of the treatments. The 9-day continuous treatments showed a better therapeutic effectiveness than those with either a 5-day, a single or a widely spaced (q 4d., 1, 5, 9) treatment. However, they were found to be marginally effective against i.p.-implanted ara-C-resistant L1210 leukemia in mice. They were also inhibitory against proliferation of human leukemia-lymphoid cells in culture. Their superior antitumor activity and resistance to cytidine deaminase suggests that they serve as a prodrug form of ara-C or ara-CMP.
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PMID:1-beta-D-arabinofuranosylcytosine conjugates of corticosteroids as potential antitumor agents. 668 55

We have previously shown that erythroid differentiation of Friend murine leukemia cells by dimethylsulfoxide results in a decrease in sialic acid content and net negative surface charge. The mechanism responsible for the decrease in sialic acid content was examined by measuring the synthesis of sialic acid from N-acetylmannosamine and its catabolic removal from sialoconjugates during the maturation process. A decrease in the incorporation of N-[3H]acetylmannosamine into sialoglycoconjugates occurred as early as 12 h after exposure to dimethylsulfoxide. Radioactivity incorporated into sialoglycoconjugates was relatively stable in untreated and dimethyl-sulfoxide-treated cells, implying that catabolic removal of sialic acid residues was not a factor in the decreased surface sialic acid content of differentiated erythroleukemia cells. In addition, no difference existed between control and treated cells in sialyltransferase activity. Significant decreases occurred, however, in the incorporation of radioactivity from N-[3H]acetylmannosamine into N-acetylneuraminic acid, CMP-N-acetylneuraminic acid and a material tentatively identified as N-acetylmannosamine-6-phosphate, 48 h after the addition of dimethylsulfoxide. The decrease in sialic acid biosynthesis in differentiated erythroleukemia cells was reflected by an 83% decrease in the amount of radioactively-labeled sialic acid released by neuraminidase treatment of cells exposed to dimethylsulfoxide. These findings are consistent with a cellular aging phenomenon triggered by the polar solvent-induced differentiation of the leukemic cells into more mature forms.
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PMID:Synthesis of sialoglycoconjugates during dimethylsulfoxide-induced erythrodifferentiation of friend leukemia cells. 705 15

Lipophilic 5'-(alkyl phosphate) esters of 1-beta-D-arabinofuranosylcytosine (ara-C) and several N4-acyl and 3'-O-acyl-2,2'-anhydro derivatives of ara-C were synthesized as potential prodrugs of ara-C 5'-monophosphate (ara-CMP). Alkylphosphorylation of ara-C, N4-palmitoyl-ara-C, and N4-stearoyl-ara-C was achieved in a single continuous operation by allowing the nucleoside to react with POCl3 in trimethyl or triethyl phosphate and adding the appropriate anhydrous alcohol directly to the intermediate phosphorodichloridate without isolation. Similar reaction of cytidine yielded cytidine 5'-(alkyl phosphate) esters, which on treatment with myristoyl or palmitoyl chloride in the presence of boron trifluoride gave 3'-O-acyl-2,2'-anhydro-ara-C 5'-(alkyl phosphate) esters. Ara-C 5'-(n-butyl phosphate) (1b), N4-palmitoyl-ara-C 5'-(n-butyl phosphate) (1h), and 2,2'-anhydro-3'-O-palmitoyl-ara-C 5'-(n-butyl phosphate) (2h) were tested against L1210/ara-C leukemia in mice in the hope that this kinase-deficient tumor would respond to treatment with these "prephosphorylated" derivatives, but no activity was observed. Of the simple 5'-(alkyl phosphate) esters tested in culture against l1210 leukemic cells, only ara-C 5'-(glyceryl phosphate) (1g) showed toxicity comparable to ara-CMP (ID50 = 0.35 and 0.65 microM, respectively), suggesting that beta-hydroxyalkyl phosphate esters may be worthwhile to examine further as prodrugs of ara-CMP.
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PMID:Lipophilic 5'-(alkyl phosphate) esters of 1-beta-D-arabinofuranosylcytosine and its N4-acyl and 2,2'-anhydro-3'-O-acyl derivatives as potential prodrugs. 705 24

Ara-CMP-Stearate (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate, YNK 01, Fosteabine) is the orally applicable prodrug of cytosine-arabinoside (Ara-C). During a phase I study in patients with advanced low-grade non-Hodgkin lymphomas or acute myeloid leukemia, the pharmacokinetic parameters of Ara-CMP-Stearate (kindly provided by ASTA Medica, Frankfurt, Germany) were determined by HPLC analysis. Seventy-two hours after a first starting dose which served for the determination of baseline pharmacokinetic parameters, Ara-CMP-Stearate was administered over 14 days by daily oral application. Ara-CMP-Stearate was started at a dose of 100 mg/day and was escalated in subsequent patients to 200 mg/day and 300 mg/day. Plasma and urine concentrations of Ara-CMP-Stearate, Ara-C and Ara-U were measured during the initial treatment phase and within 72 h after the end of the 14-day treatment cycle. So far six patients have been treated with 100 mg/day, three with 200 mg/day and another six with 300 mg/day. One patient was treated consecutively with 100 mg, 300 mg and 600 mg. Fitting the results of the plasma concentration measurements of Ara-CMP-Stearate to a one-compartment model, the following pharmacokinetic parameters were obtained (average and variation coefficient VC). Ara-CMP-Stearate dose-independent parameters: lag time = 1.04 h (0.57); tmax = 5.72 h (0.30); t1/2 = 9.4 h (0.36). Dose-dependent parameters: at 100 mg: AUC = 1099 ng/h/ml (0.31); concentration(max) = 53.8 ng/ml (0.28); at 200 mg: AUC = 2753 ng/h/ml (0.32); concentration(max) = 154.8 ng/ml (0.46); at 300 mg: AUC = 2940 ng/h/ml (0.66); concentration(max) = 160.0 ng/ml (0.59). The long lag time and late tmax can be explained by resorption in the distal part of the small intestine. No Ara-CMP-Stearate was detected in urine samples (limit of detection = 500 pg/ml). Pharmacokinetic parameters of Ara-C following Ara-CMP-Stearate application showed the following characteristics: t1/2 = 24.3 h (0.39); AUC (100 mg) = 262 ng/h/ml (0.93); AUC (200 mg) = 502 ng/h/ml (0.87); AUC (300 mg) = 898 ng/h/ml (1.07). Since Ara-CMP-Stearate causes intravascular hemolysis after intravenous administration, it was not possible to determine its bioavailability by comparing the AUC after oral and i.v. application. Instead, the renal elimination of Ara-U, as the main metabolite of Ara-C was measured during the first 72-h period and after the last application.(ABSTRACT TRUNCATED AT 400 WORDS)
Leukemia 1995 Jun
PMID:Pharmacokinetics of Ara-CMP-Stearate (YNK01): phase I study of the oral Ara-C derivative. 759 74

To elucidate control mechanisms of O-glycan biosynthesis in leukemia and to develop biosynthetic inhibitors we have characterized core 2 UDP-GlcNAc:Gal beta 1-3GalNAc-R(GlcNAc to GalNAc) beta 6-N-acetylglucosaminyltransferase (EC 2.4.1.102; core 2 beta 6-GlcNAc-T) and CMP-sialic acid: Gal beta 1-3GalNAc-R alpha 3-sialyltransferase (EC 2.4.99.4; alpha 3-SA-T), two enzymes that are significantly increased in patients with chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML). We observed distinct tissue-specific kinetic differences for the core 2 beta 6-GlcNAc-T activity; core 2 beta 6-GlcNAc-T from mucin secreting tissue (named core 2 beta 6-GlcNAc-T M) is accompanied by activities that synthesize core 4 [GlcNAc beta 1-6(GlcNAc beta 1-3)GalNAc-R] and blood group I [GlcNAc beta 1-6(GlcNAc beta 1-3)Gal beta-R] branches; core 2 beta 6-GlcNAc-T in leukemic cells (named core 2 beta-GlcNAc-T L) is not accompanied by these two activities and has a more restricted specificity. Core 2 beta 6-GlcNAc-T M and L both have an absolute requirement for the 4- and 6-hydroxyls of N-acetylgalactosamine and the 6-hydroxyl of galactose of the Gal beta 1-3GalNAc alpha-benzyl substrate but the recognition of other substituents of the sugar rings varies, depending on the tissue. alpha 3-sialyltransferase from human placenta and from AML cells also showed distinct specificity differences, although the enzymes from both tissues have an absolute requirement for the 3-hydroxyl of the galactose residue of Gal beta 1-3GalNAc alpha-Bn. Gal beta 1-3(6-deoxy)GalNAc alpha-Bn and 3-deoxy-Gal beta 1-3GalNAc alpha-Bn competitively inhibited core 2 beta 6-GlcNAc-T and alpha 3-sialyltransferase activities, respectively.
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PMID:Processing O-glycan core 1, Gal beta 1-3GalNAc alpha-R. Specificities of core 2, UDP-GlcNAc: Gal beta 1-3 GalNAc-R(GlcNAc to GalNAc) beta 6-N-acetylglucosaminyltransferase and CMP-sialic acid: Gal beta 1-3GalNAc-R alpha 3-sialyltransferase. 829 5

The effectiveness of arabinosylcytosine (ara-C) for the treatment of acute myelogenous leukemia (AML) depends on the formation of its active metabolite, the triphosphate of ara-C (ara-CTP). Using biochemical modulation strategies to increase the accumulation of ara-CTP in leukemia blasts, a clinical protocol was designed combining 2-chlorodeoxyadenosine (CdA), an inhibitor of ribonucleotide reductase, and ara-C for adults with AML. The protocol stipulated an infusion of 1 g/m2 of ara-C over 2 hours on day 1. A continuous infusion of CdA (12 mg/m2/d) begun 24 hours later and continued for 5 days. Identical doses of ara-C were administered on days 3, 4, 5, and 6. Pharmacokinetic and pharmacodynamic interactions between CdA and ara-C during therapy were investigated. To complement these studies, molecular actions of the triphosphate of ara-C and CdA on DNA extension by human DNA polymerase alpha in an in vitro model system was conducted. In the circulating leukemia blasts of 7 of the 9 patients studied, ara-CTP pharmacokinetics showed a median 40% increase in the rate of ara-CTP accumulation after 24 hours of CdA infusion. The ex vivo effect of CdA on accumulation of ara-CTP in AML blasts was similar to that during therapy except that the enhancement was less. The DNA synthetic capacity of the circulating blasts was inhibited to a greater extent by administration of CdA and ara-C in combination than by either one alone. Additionally the lowered level of DNA synthesis was maintained until the next infusion of ara-C. Endogenous levels of deoxynucleotides increased 24 hours after ara-C infusion. Administration of CdA in general lowered the concentrations of all dNTPs. DNA pol alpha incorporated CdATP and ara-CTP with high affinity in a DNA primer extending over an oligonucleotide template of defined sequence. Human DNA polymerase alpha extended DNA primers terminated by CdA monophosphate (CdAMP) at its 3'-end by incorporating ara-C monophosphate (ara-CMP). The tandem incorporation of CdAMP and ara-CMP resulted in nearly complete inhibition of DNA primer extension. The insertion of two analogs in sequence, inhibition of ribonucleotide reductase, and the metabolic potentiation of ara-CTP by CdA infusion may be responsible for sustained inhibition of DNA synthesis in the circulating leukemia blasts during therapy with this combination regimen.
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PMID:Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogenous leukemia: pharmacokinetic, pharmacodynamic, and molecular interactions. 854 50

Fludarabine and 1-beta-D-arabinofuranosylcytosine (ara-C) are effective nucleoside analogues for the treatment of leukemias when used as single agents or together. Recent trials of the fludarabine and ara-C therapy with or without growth factors suggested an improved clinical response by combining fludarabine and ara-C. The activity of these antimetabolites depends on their phosphorylation to the respective triphosphates, F-ara-ATP and ara-CTP. The principal mechanism through which these triphosphates cause cytotoxicity is incorporation into DNA and inhibition of further DNA synthesis. A model system of DNA primer extension on a defined template sequence was used to quantitate the consequences of incorporation of one or two analogues by human DNA polymerase alpha (pol alpha). The template (31-mer) was designed so that DNA pol alpha incorporated six deoxynucleotides (alternately G and T) on the 17-mer primer, followed by insertion of an A and then a C. The primer was then elongated with G and T to the full-length product. The apparent Kms of DNA pol alpha to incorporate these analogues (0. 053 and 0.077 microM, respectively) were similar to the Km for dCTP (0.037 microM) and dATP (0.044 microM), suggesting that the enzyme recognized these analogues and incorporated them efficiently on the growing DNA primer. The velocity of extension (Vmax) of these primers ranged between 0.53 and 0.77%/min when normal nucleotides were present. Once inserted at the 3'-terminus, F-ara-AMP or ara-CMP were poor substrates for extension. However, in reactions lacking dCTP and dATP and with high concentrations of ara-CTP, ara-CMP was inserted by pol alpha after incorporation of the F-ara-AMP residue. This tandem incorporation of the two analogues resulted in almost complete inhibition (99.3%) of further extension of the primer. In the presence of competing deoxynucleotides, each analogue resulted in a dose-dependent inhibition of DNA synthesis. When present together, inhibition of the primer elongation was more than additive at low concentrations of analogue triphosphates. Based on these results and the intracellular pharmacokinetics of ara-CTP and F-ara-ATP in leukemia blasts, we propose a pharmacodynamic model to explain interactions between these analogues during combination chemotherapy.
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PMID:Incorporation of fludarabine and 1-beta-D-arabinofuranosylcytosine 5'-triphosphates by DNA polymerase alpha: affinity, interaction, and consequences. 981 18

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

Surface expressed negatively charged sialoglycans contribute to the regulation of adhesive cellular interactions and are thus involved in the growth and differentiation of hematopoietic progenitor cells. In particular, the cell surface sialylation state may govern the liberation of CD34+ hematopoietic precursors from bone marrow stroma cells and extracellular matrix. In order to assess the overall surface sialylation of live human CD34+ hematopoietic precursor cells, we applied a previously described flow cytometric enzyme assay. Cells with and without sialidase pretreatment were incubated in the presence of fluorescent CMP-sialic acid and exogenous ST6GalI. Thus sialylation of surface-expressed lactosamine residues was analysed. We demonstrated that surface lactosamines of CD34+ precursors derived from bone marrow and peripheral blood are over 95% sialylated, predominantly in alpha2-6 linkage. These results are in accordance with flow cytometric analysis of surface lectin staining. Sialic acid specific lectins MAA and SNA were strongly bound whereas SBA, VVA, and PNA became reactive only after sialidase pretreatment. CD34+ leukemia cell lines TF1 and KG1a also showed a high degree of surface sialylation, whereas cell line KG1 expressed to the largest extent free lactosamines. In these cell lines, alpha2-6 and alpha2-3 sialylated residues were present in equal amounts. In a variation of the flow cytometric enzyme assay, live cells were incubated without exogenous STGal I to measure the activity of endogenous ecto-sialyltransferase. Ecto sialyltransferase activity was observed in all CD34+ cells which was able to resialylate major surface glycoproteins such as HLA Class I, CD45, CD43, and CD34. The ecto-sialyltransferase may serve to maintain or increase surface sialylation rapidly without de novo synthesis.
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PMID:Cell surface sialylation and ecto-sialyltransferase activity of human CD34 progenitors from peripheral blood and bone marrow. 1575 Jul 86

Enzyme deficiency in the salvage pathway of deoxyribonucleotide synthesis in mitochondria can cause mtDNA depletion syndromes. We have identified a human mitochondrial UMP-CMP kinase (UMP-CMPK, cytidylate kinase; EC 2.7.4.14), designated as UMP-CMP kinase 2 (UMP-CMPK2). The C-terminal domain of this 449-amino acid protein contains all consensus motifs of a nucleoside monophosphate kinase. Phylogenetic analysis showed that UMP-CMPK2 belonged to a novel nucleoside monophosphate kinase family, which was closer to thymidylate kinase than to cytosolic UMP-CMP kinase. Subcellular localization with green fluorescent protein fusion proteins illustrated that UMP-CMPK2 was localized in the mitochondria of HeLa cells and that the mitochondrial targeting signal was included in the N-terminal 22 amino acids. The enzyme was able to phosphorylate dUMP, dCMP, CMP, and UMP with ATP as phosphate donor, but the kinetic properties were different compared with the cytosolic UMP-CMPK. Its efficacy to convert dUMP was highest, followed by dCMP, whereas CMP and UMP were the poorest substrates. It also phosphorylated the monophosphate forms of the nucleoside analogs ddC, dFdC, araC, BVDU, and FdUrd, which suggests that UMP-CMPK2 may be involved in mtDNA depletion caused by long term treatment with ddC or other pyrimidine analogs. UMP-CMPK2 mRNA expression was exclusively detected in chronic myelogenous leukemia K-562 and lymphoblastic leukemia MOLT-4 among eight studied cancer cell lines. Particular high expression in leukemia cells, dominant expression in bone marrow, and tight correlation with macrophage activation and inflammatory response suggest that UMP-CMPK2 may have other functions in addition to the supply of substrates for mtDNA synthesis.
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PMID:Human UMP-CMP kinase 2, a novel nucleoside monophosphate kinase localized in mitochondria. 1799 54


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