The kinetic dissection of transport from metabolic trapping during substrate uptake by intact cells. Uridine uptake by quiescent and serum-activated nil 8 hamster cells and their murine sarcoma virus-transformed counterparts

Heichal, Ora; Ish-Shalom, Dvorah; Koren, Ruth; Stein, Wilfred D.

doi:10.1016/0005-2736(79)90363-8

Cited by 41 publications

(22 citation statements)

References 8 publications

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“…Movement of nu-cleoside and many of their analogs across the plasma membrane in many cell types is mediated by a nucleoside specific transport mechanism. Cytosine arabinoside is a substrate for this carrier system (11)(12)(13)(14)(15) that is reversible, nonconcentrative, and has a broad specificity for pyrimidine and purine nucleosides. However, the affinity of the nucleoside carrier in leukemic cells is less for araC than for its naturally occurring pyrimidine analog, deoxycytidine.…”

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confidence: 99%

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Cytosine Arabinoside Influx and Nucleoside Transport Sites in Acute Leukemia

Wiley¹,

Jones²,

Sawyer³

et al. 1982

J. Clin. Invest.

184

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A B S T R A C T Although cytosine arabinoside (araC)can induce a remission in a majority of patients presenting with acute myeloblastic leukemia (AML), a minority fail to respond and moreover the drug has less effect in acute lymphoblastic leukemia (ALL). The carrier-mediated influx of araC into purified blasts from patients with AML, ALL, and acute undifferentiated leukemia (AUL) has been compared to that of normal lymphocytes and polymorphs. Blasts showed a larger mediated influx of araC than mature cells, since mean influxes for myeloblasts and lymphoblasts were 6-and 2.3-fold greater than polymorphs and lymphocytes, respectively. Also, the mean influx for myeloblasts was fourfold greater than the mean for lymphoblasts. The number of nucleoside transport sites was estimated for each cell type by measuring the equilibrium binding of [3H]nitrobenzylthioinosine (NBMPR), which inhibits nucleoside fluxes by binding with high affinity to specific sites on the transport mechanism. The mean binding site numbers for myeloblasts and lymphoblasts were 5-and 2.8-fold greater, respectively, than for the mature cells of the same maturation series. The mean number of NBMPR binding sites for myeloblasts was fourfold greater than for lymphoblasts. Patients with AUL were heterogeneous since blasts from some gave values within the myeloblastic range and others within the lymphoblastic range. The araC influx correlated closely with the number of NBMPR binding sites measured in the same cells on the same day. Transport parameters were measured on blasts from 15 patients with AML or AUL who were then treated with standard induction therapy containing araC. Eight patients entered complete remission, while seven failed therapy, among whom

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confidence: 99%

“…Both the influx of araC as well as the number of NBMPR binding sites have been measured on blasts prepared from fresh peripheral blood. In a group of 15 (21). Duration of araC infusion was shortened to 5 d for second and subsequent courses (22).…”

mentioning

confidence: 99%

Cytosine Arabinoside Influx and Nucleoside Transport Sites in Acute Leukemia

Wiley¹,

Jones²,

Sawyer³

et al. 1982

J. Clin. Invest.

184

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“…The various factors which may influence the level of araCTP attained include transport (step 1), phosphorylation (steps 2, 3, and 4), and deamination (steps 5 and 6). At low concentrations of exogenous nucleoside, membrane transport appears to be a major rate-limiting step for nucleotide formation (32). Deoxycytidine kinase (step 2) may also have a pivotal role in araCTP formation, both through variations in the total enzyme activity in cells and also through feedback inhibition by dCTP on kinase-mediated phosphorylation of araC (33).…”

Section: Discussionmentioning

confidence: 99%

Cytosine arabinoside transport and metabolism in acute leukemias and T cell lymphoblastic lymphoma.

Wiley¹,

Taupin²,

Jamieson³

et al. 1985

J. Clin. Invest.

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Cytosine arabinoside (araC) has proven efficacy in acute myeloid leukemia (AML), but its place in the treatment of acute lymphoblastic leukemia (ALL) and T lymphoblastic lymphoma is uncertain. The therapeutic potential of araC has been assessed in patients with AML, ALL, and T lymphoblastic lymphoma by measuring the conversion of araC to its active metabolite, the 5-triphosphate of araC (araCTP), in purified blasts from patients as well as in normal polymorphs and lymphocytes. In all leukemias, araCTP was the major intracellular metabolite of araC. The highest araCTP formation was in blasts from T lymphoblastic lymphoma, which formed threefold more nucleotide than myeloblasts, and in turn myeloblasts formed twofold more araCTP than lymphoblasts from ALL. The mean araCTP formation in myeloblasts was sixfold greater than polymorphs, but in contrast, lymphoblasts and lymphocytes formed low and similar amounts of this nucleotide. Reasons for the sixfold range in araCTP accumulation in the various leukemic blasts were studied.

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“…The activation of uridine uptake into quiescent NIL 8 or 3T3 cells, by serum (or insulin) has been studied extensively in this [4,5] and other laboratories [l-3]. Two experimental procedures were applied: the cells were either incubated in DMEM containing the activator prior to the uptake experiment, or exposed to the activator at the same time as the labelled uridine.…”

Section: Uptake Experimentsmentioning

confidence: 99%

“…Parallel cultures were incubated for 90 min [5] at 37°C in PBS, PBS containing 0.5 mM MgClz and 0.7 mM CaCl* , DMEM, and a buffer containing 150 mM NaCl and 30 mM Hepes (pH 7.4). The incubation mixtures contained either 10% dialyzed newborn calf serum or the buffer itself.…”

Section: Minutesmentioning

confidence: 99%