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 distribution of arabinosylcytosine (ara-C) and its metabolites has been measured in the liver, small intestine, spleen, and kidney of mice inoculated ip 5-6 days earlier with L1210 leukemia cells. Two major metabolites were found in the tissues--the nucleotides and the deaminated inactive product, arabinosyluracil (ara-U). The decay curve of ara-C in most of these tissues was curvilinear; the ara-C half-lives estimated from the terminal phases were 8. 11, 12, and 12 hr for spleen, kidney, intestine, and liver tissues, respectively. The ara-C half-life was not correlated with the deoxycytidine deaminase activity in the tissues. However, the deaminase activity in vitro correlated well with the amount of ara-U present in vivo. Similar analyses were made for L1210 leukemic cells and ascites fluid. A high nucleotide level was found in the cells and a significant amount of nucleotides was also identifiable in the ascites fluid. The activities of deoxycytidine kinase, but not of deoxycytidine deaminase, in host tissues of mice inoculated with L1210 leukemic cells sensitive to ara-C were greater than in those of normal mice. The phosphorylating activities in vitro correlated with the amount of nucleotide present in vivo in mice bearing L1210 leukemic cells. However, the infiltration of leukemic cells containing high kinase activities into the host tissues accounted for most, if not all, of the nucleotide level in these tissues. This is further evidenced by the fact that inoculating mice with L1210 leukemic cells resistant to ara-C did not alter the kinase activity or nucleotide levels of the host tissues; these resistant cells contain negligible amounts of ara-C phosphorylating activities.
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PMID:Correlation of mouse tissue distribution of arabinosylcytosine in vivo with enzymatic activities in vitro. 0 36

5-Azacytidine is more active when administered parenterally than orally in the treatment of L1210 leukemic mice. Oral coadministration of tetrahydrouridine, a pyrimidine nucleoside deaminase inhibitor with no intrinsic antitumor activity, greatly increases the oral activity of 5-azacytidine. 5-azacytidine (or cytotoxic equivalent) blood levels in BDF mice are much higher after oral administration of the 5-azacytidine-tetrahydrouridine combination than when 5-azacytidine is administered alone by the same route. The therapeutic results (L1210 leukemia) achieved with the oral combination are similar to those observed with parenteral 5-azacytidine alone.
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PMID:Enhancement by tetrahydrouridine (NSC-112907) of the oral activity of 5-azacytidine (NSC-102816) in L1210 leukemic mice. 5 11

The potent adenosine deaminase inhibitor 2'-deoxycoformycin ((R)-3-(2-deoxy-beta-D-erythropentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol) inhibits the enzymic inactivation and potentiates the cytotoxic activity of a variety of adenosine analogs in the P388 murine leukemia cell culture system. The activity of all seven adenosine analogs examined was enhanced by 2'-deoxycoformycin with the exception of tubercidin (7-deaza-adenosine) which is not a substrate for the deaminase. In vivo, 2'-deoxy-coformycin potentiated the antineoplastic activity of 9-beta-D-xylofuranosyladenine in mice with P388 murine leukemia.
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PMID:Enhancement of the biological activity of adenosine analogs by the adenosine deaminase inhibitor 2'-deoxycoformycin. 84 Aug 92

An integrated mathematic computer-based model of the pharmacokinetics, intracellular enzyme kinetics, and cell kinetics of the treatment of L1210 leukemia by cytosine arabinoside (ara-C) is described. The compartment model of Bischoff and Dedrick is extended to the intracellular level by inclusion of equations describing the phosphorylation, dephosphorylation, and deamination of ara-C with enzymatic feedback control. The activities of kinase, deaminase, and phosphatase are explicitly included in the models and are estimated from relevant data. Cell proliferation is described by a continuous-flow mathematic model in which cellular maturation and cell-to-cell variability in maturation rates are key variables. Cell proliferation is related to intracellular biochemistry through mathematic expressions which relate cell lethality and progression delay to the time course of intracellular ara-CTP. In vitro and in vivo experiments performed in a number of laboratories are compared by simulation. The most sensitive parameters in dose-response and cell-survival simulations are deoxycytidine kinase activity, ara-CTP half-life, renal clearance of ara-C, and cell-kinetic parameters for proliferation and cell killing. Progression delay is vital to the realistic simulation of divided-dose schedules. By comparative simulation we have identified areas of uncertainty which can be classified by a few additional measurements. The applications of simulations combining pharmacokinetic, biochemical, and cell-kinetic data in vitro and in vivo are discussed, exploring consistency among different measurements, and relating experimental protocols to clinical treatment.
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PMID:Computer simulation of leukemia therapy: combined pharmacokinetics, intracellular enzyme kinetics, and cell kinetics of the treatment of L1210 leukemia by cytosine arabinoside. 102 30

Deamination of the nucleoside analogues ARA-C and 5-AZA-CdR by CR deaminase results in a loss of antileukemic activity. To prevent the inactivation of these analogues, inhibitors of CR deaminase may prove to be useful agents. In the present study we investigated the effects of the deaminase inhibitors Zebularine, 5-F-Zebularine, and diazepinone riboside on the deamination of CR, ARA-C, and 5-AZA-CdR using highly purified human CR deaminase (EC 3.5.4.5). These inhibitors produced a competitive type of inhibition with each substrate, the potency of which followed the patterns diazepinone riboside greater than 5-F-Zebularine and THU greater than Zebularine. 5-AZA-CdR was more sensitive than ARA-C to the inhibition produced by these deaminase inhibitors. The inhibition constants for diazepinone riboside lay in the range of 5-15 nM, suggesting that this inhibitor could be an excellent candidate for use in combination chemotherapy with either ARA-C or 5-AZA-CdR in patients with leukemia.
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PMID:Potent inhibitors for the deamination of cytosine arabinoside and 5-aza-2'-deoxycytidine by human cytidine deaminase. 137 34

In summary, there are compelling laboratory and clinical data indicating that higher doses of ara-C than are currently used in SDaC protocols constitute optimal therapy. The cellular pharmacokinetics of ara-C are optimized at extracellular drug concentrations in the 10 to 15 mumol/L range. At these concentrations, transport rates are no longer rate-limiting, and ara-C phosphorylation capacity is saturated. The prime determinants of ara-C effect then shift to multiple intracellular events including anabolism to nucleotides, catabolism via deamination by Cyd-dCyd deaminase and dCMP deaminase, half-life of ara-CTP, the extent of incorporation into DNA, and the half-life of ara-CMP residues in DNA. It is postulated that at these high doses an additional effect of ara-C occurs on the cell membrane through affects on membrane phospholipid synthesis. This effect may contribute to the brisk cell lysis associated with HiDaC treatment. When administered as repetitive doses of 3 g/m2 over a 1- to 3-hour period, systemic deamination of ara-C gives rise to high plasma concentrations of ara-U. This metabolite has a long plasma half-life and, at least in the mouse, is concentrated in the liver and kidneys. High concentrations in these organs retard the further catabolism of ara-C and thus increase the systemic AUC providing a longer exposure period to the drug. A similar mechanism may obtain in patients treated with HiDaC. The observed decreased clearance of ara-C when administered in gram versus milligram doses and the long-terminal gamma-phase in plasma clearance of the drug associated with HiDaC usage quite probably reflects this effect of ara-U in patients. Additionally, by some as yet unknown mechanism, high concentrations of ara-U cause accumulation of leukemia cells in S-phase, the phase of the cell cycle wherein ara-C is maximally effective. This effect of ara-U may add to the cytokinetic effects initiated by rapid cytoreduction, which summate in the observed enhancement of the proliferative fraction of residual leukemia cells on day 8. The effect of a second course of therapy at this time is thereby enhanced. These dose-related and metabolite-drug interactions that occur when ara-C is given at high doses constitute a means for "self-potentiation" and may thus contribute to its overall therapeutic efficacy.
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PMID:Effect of dose on the pharmacokinetic and pharmacodynamic effects of cytarabine. 178 Jul 54

The sensitivity of human myelogenous leukemia cells to 1-beta-D-arabinofuranosylcytosine (ara-C) during induction of differentiation was examined. Treatment with hemin greatly increased the sensitivity of erythroid leukemia cells to ara-C. The enhancement of ara-C sensitivity by hemin was not as remarkable in nonerythroid leukemia cells. Hemin altered the metabolism of ara-C in human erythroleukemia K562 cells by reducing ara-C deaminase activity, increasing intracellular accumulation of ara-C, and activating the nucleoside kinases. These alterations may be involved in the enhancing effect of hemin on sensitivity of ara-C. These results suggest that some inducers of differentiation potentiate the antileukemic effect of ara-C on human erythroleukemia cells.
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PMID:Hemin enhances the sensitivity of erythroleukemia cells to 1-beta-D-arabinofuranosylcytosine by both activation of deoxycytidine kinase and reduction of cytidine deaminase activity. 187 97

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.
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PMID:Effect of tetrahydrouridine and deoxytetrahydrouridine on the interaction between 2'-deoxycytidine and 1-beta-D-arabinofuranosylcytosine in human leukemia cells. 203 Jun 1

A polytropic recombinant retrovirus containing the envelope gene of Friend mink cell focus-inducing virus plus the remainder of the genome of an amphoropic murine leukemia virus was propagated on mouse embryo fibroblasts and mink lung cells. Virus particles, metabolically labeled with [2-3H]mannose, were harvested from the culture supernatants and lysed with detergents. The viral envelope glycoprotein was isolated from the lysates by immunoaffinity chromatography and purified by preparative SDS/PAGE. Oligosaccharides were liberated by sequential treatment of tryptic glycopeptides with endo-beta-N-acetylglucosaminidase H and peptide-N4-(N-acetyl-beta-glucosaminyl) asparagine amidase F and fractionated by high-performance liquid chromatography. Individual glycans were characterized chromatographically, by methylation analyses and in part, by enzymic microsequencing. The results demonstrated that viral glycoproteins, synthesized in mouse embryo fibroblasts, carried as major constituents partially fucosylated diantennary, 2,4- and 2,6-branched triantennary and tetraantennary complex type N-glycans with 0-4 sialic acid residues and only small amounts of high-mannose type species with 5-9 mannose residues. As a characteristic feature, part of the complex type glycans contained additional Gal(alpha 1-3) substituents. Glycoprotein obtained from virions propagated on mink lung cells, contained partially fucosylated diantennary and 2,4-branched triantennary oligosaccharides with 1-3 sialic acid residues, in addition to trace amounts of high-mannose type species with 8 or 9 mannose residues. Thus, the results reveal that predominantly, the complex type N-glycans of the retroviral envelope glycoprotein display cell-specific variations including differences in oligosaccharide branching, sialylation and substitution by additional Gal(alpha 1-3) residues.
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PMID:Glycosylation of the envelope glycoprotein from a polytropic murine retrovirus in two different host cells. 217 68

Though data from cell lines are abundant, the reason for the development of resistance to 1-beta-D arabinofuranosylcytosine (ara-C) in vivo remains unresolved. A broad interpatient variation of metabolic parameters has further complicated interpretation of the results. The present study compares ara-C metabolism in leukemic blasts of two patients with newly diagnosed disease, before and after repeated treatment with ara-C containing chemotherapy regimens in vivo. Membrane transport of ara-C was unchanged after treatment. In addition, cell-free extracts of blasts obtained after treatment failure showed an unchanged cytidine deaminase activity. Though deoxycytidine kinase activity in cell extracts was unaltered or increased after treatment failure, the activity in situ, measured as the rate of 1-beta-D-arabinofuranosylcytosine triphosphate (ara-CTP) formation, was decreased. This could be shown to be due to an expansion of the deoxycytidine triphosphate (dCTP) pool. The severalfold increase in dCTP pool was accompanied by a decrease in thymidine triphosphate (dTTP) pool and correlated with a decrease in deoxycytidylate deaminase (dCMP-deaminase) activity in cell free extracts. Low dCMP-deaminase activity had been shown to confer an ara-C resistant phenotype to cell lines in vitro. Data presented in this paper show that a selection for leukemic blasts with low dCMP-deaminase activity can also be favored by ara-C containing treatment regimens in vivo. Our data suggest that this mechanism might contribute to treatment failure.
Leukemia 1990 Nov
PMID:Concordant changes of pyrimidine metabolism in blasts of two cases of acute myeloid leukemia after repeated treatment with ara-C in vivo. 223 89


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