Nucleoside transporters in chronic lymphocytic leukaemia

Pastor‐Anglada, Marçal; Molina‐Arcas, Míriam; Casado, F. Javier; Bellosillo, Beatríz; Colomer, Dolors; Gil, Joan

doi:10.1038/sj.leu.2403271

Cited by 93 publications

(84 citation statements)

References 91 publications

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“…15,16 Leukemia cells appear to express both CNT-and ENT-type transporter mRNAs. 17 Primary CLL cells express hENT1, hENT2, hCNT2 and hCNT3. hCNT3 and hCNT2 are high-affinity Na þ -dependent NT showing broad selectivity and purine preference, respectively.…”

Section: Introductionmentioning

confidence: 99%

Equilibrative nucleoside transporter-2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells

et al. 2004

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Fludarabine is considered the treatment of choice for most patients with chronic lymphocytic leukemia (CLL). We have analyzed the role of plasma membrane transporters in nucleoside-derived drug bioavailability and action in CLL cells. Among the known plasma membrane transporters, we have previously observed a significant correlation between fludarabine uptake via ENT carriers and ex vivo sensitivity of CLL cells to fludarabine, although mRNA amounts of the equilibrative nucleoside transporters hENT1 and hENT2 do not show any predictive response to treatment. In this study, using polyclonal monospecific antibodies we have observed a significant correlation between the expression of hENT2 by Western blot and fludarabine uptake via hENT carriers and also with ex vivo sensitivity of CLL cells to fludarabine. These results suggest that the equilibrative nucleoside transporter hENT2 plays a role in fludarabine responsiveness in CLL patients.

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Section: Introductionmentioning

confidence: 99%

Equilibrative nucleoside transporter-2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells

et al. 2004

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“…Uncontrolled proliferation processes do not appear to be implicated in the development of CLL and, in accordance with what has been discussed above, hENT1 expression contributes only slightly to fludarabineinduced cytotoxicity in CLL cells, 12,14 even though fludarabine is a hENT1 substrate. 11 In fact, the levels of hENT2 protein correlate with the ex vivo cytotoxicity induced by this nucleoside analog in CLL cells. 12 In this study we were able to show that the transcriptomic response of CLL cells to fludarabine was poorly sensitive to nucleoside transport inhibition triggered by NBTI, a finding that is consistent with hENT2 playing a major role in the genomic response of CLL cells to fludarabine.…”

Section: Discussionmentioning

confidence: 99%

“…9,10 CNT proteins mediate high-affinity, concentrative nucleoside transport into cells, whereas equilibrative transporters are responsible for the facilitative uptake of nucleosides and nucleosidederived drugs, with broad selectivity but lower affinity than that shown by CNT proteins. 11 CLL cells express hENT1, hENT2, hCNT2 and hCNT3 mRNA, although most of the biological activity responsible for fludarabine uptake is associated with hENT transporters. 12 This is probably due to the fact that the hCNT3 protein is localized mostly in intracellular compartments of CLL cells, 13 while fludarabine is not a suitable permeant for hCNT2, 11 a transporter protein that is functional at the plasma membrane of CLL cells.…”

Section: Introductionmentioning

confidence: 99%

“…11 CLL cells express hENT1, hENT2, hCNT2 and hCNT3 mRNA, although most of the biological activity responsible for fludarabine uptake is associated with hENT transporters. 12 This is probably due to the fact that the hCNT3 protein is localized mostly in intracellular compartments of CLL cells, 13 while fludarabine is not a suitable permeant for hCNT2, 11 a transporter protein that is functional at the plasma membrane of CLL cells. 12 In fact, although both hENT1 and hENT2 can mediate fludarabine internalization, hENT2 but not hENT1 protein levels have recently been correlated with ex vivo sensitivity of CLL cells to this nucleoside analog.…”

Section: Introductionmentioning

confidence: 99%

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Identification of TIGAR in the equilibrative nucleoside transporter 2-mediated response to fludarabine in chronic lymphocytic leukemia cells

López‐Guerra

Trigueros-Motos²,

Molina‐Arcas³

et al. 2008

Haematologica

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BackgroundThe nucleoside analogue fludarabine is used in the treatment of chronic lymphocytic leukemia. It triggers p53-mediated apoptosis, although the mutational status of p53 does not fully account for heterogeneity in responsiveness to treatment. The aim of this study was to identify new genes implicated in fludarabine action as well as to determine the role of equilibrative nucleoside transporters (ENT) in the transcriptomic response triggered by this drug in chronic lymphocytic leukemia cells bearing wild type p53.

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“…Their uptake into cells is largely dependent on the activity of human equilibrative nucleoside transporters (hENTs) and human concentrative nucleoside transporters (hCNTs) [15][16][17][18]. The hENTs are capable of transporting pyrimidine and purine nucleosides from outside to inside the cell and vice versa, and are widely distributed in most human cells [19].…”

Section: Uptake By Hntsmentioning

confidence: 99%

Prolonged Versus Standard Gemcitabine Infusion: Translation of Molecular Pharmacology to New Treatment Strategy

2008

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After completing this course, the reader will be able to:1. Describe the molecular pharmacology of nucleoside analogues.2. Explain transport, metabolism, and elimination in relation to the activity of gemcitabine.3. Describe the clinical pharmacology of gemcitabine in relation to its rate of administration.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTGemcitabine is frequently used in the treatment of patients with solid tumors. Gemcitabine is taken up into the cell via human nucleoside transporters (hNTs) and is intracellularly phosphorylated by deoxycytidine kinase (dCK) to its monophosphate and subsequently into its main active triphosphate metabolite 2,2-difluorodeoxycytidine triphosphate (dFdCTP), which is incorporated into DNA and inhibits DNA synthesis. In addition, gemcitabine is extensively deaminated to 2,2-difluorodeoxyuridine, which is largely excreted into the urine. High expression levels of human equilibrative nucleoside transporter type 1 were associated with a significantly longer overall survival duration after gemcitabine treatment in patients with pancreatic cancer.Clinical studies in blood mononuclear and leukemic cells demonstrated that a lower infusion rate of gemcitabine was associated with higher intracellular dFdCTP levels. Prolonged infusion of gemcitabine at a fixed dose rate (FDR) of 10 mg/m 2 per minute was associated with a higher intracellular accumulation of dFdCTP, greater toxicity, and a higher response rate than with the standard 30-minute infusion of gemcitabine in patients with pancreatic cancer.In the current review, we discuss the molecular pharmacology of nucleoside analogues and the influence of hNTs and dCK on the activity and toxicity of gemcitabine, which is the basis for clinical studies on

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Nucleoside transporters in chronic lymphocytic leukaemia

Cited by 93 publications

References 91 publications

Equilibrative nucleoside transporter-2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells

Equilibrative nucleoside transporter-2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells

Identification of TIGAR in the equilibrative nucleoside transporter 2-mediated response to fludarabine in chronic lymphocytic leukemia cells

Prolonged Versus Standard Gemcitabine Infusion: Translation of Molecular Pharmacology to New Treatment Strategy

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