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Intracellular Disposition of Fludarabine Triphosphate in Human Natural Killer Cells

Woodahl, Erica L and Wang, Joanne and Heimfeld, Shelly and Sandmaier, Brenda M. and McCune, Jeannine S. (2009) Intracellular Disposition of Fludarabine Triphosphate in Human Natural Killer Cells. Cancer Chemotherapy and Pharmacology, 63 (5). pp. 959-964. ISSN 1432-0843

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Purpose. Fludarabine is a key component of several reduced-intensity conditioning regimens for hematopoietic cell transplantation (HCT). Shortly after reduced-intensity conditioning, the percent of donor natural killer (NK) cells has been associated with progression-free survival. Insufficient suppression of the recipient’s NK cells by fludarabine may lead to lower donor chimerism; however, the effect of fludarabine upon NK cells is poorly understood. Thus, in purified human NK cells we evaluated the uptake and activation of fludarabine to its active metabolite, fludarabine triphosphate (F-ara-ATP), and assessed the degree of interindividual variability in F-ara-ATP accumulation. Methods. Intracellular F-ara-ATP was measured in purified NK cells isolated from healthy volunteers (n = 6) after ex vivo exposure to fludarabine. Gene expression levels of the relevant transporters and enzymes involved in fludarabine uptake and activation were also measured in these cells. Results. F-ara-ATP accumulation (mean ± s.d.) was 6.00 ± 3.67 pmol/1x106 cells/4 hours, comparable to average levels previously observed in CD4+ and CD8+ T-lymphocytes. We observed considerable variability in F-ara-ATP accumulation and mRNA expression of transporters and enzymes relevant to F-ara-ATP accumulation in NK cells from different healthy volunteers. Conclusions. Human NK cells have the ability to form F-ara-ATP intracellularly and large interindividual variability was observed in healthy volunteers. Further studies are needed to evaluate whether F-ara-ATP accumulation in NK cells are associated with apoptosis and clinical outcomes.

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DOI: 10.1007/s00280-008-0829-0
PubMed ID: 18781301
PMCID: PMC2648818
Grant Numbers: HL91744, CA18029, CA15704, CA78902, DK56465, HL36444
Keywords or MeSH Headings: 5'-Nucleotidase/genetics/metabolism; Arabinonucleotides/*metabolism; Equilibrative Nucleoside Transporter 1/genetics/metabolism; Equilibrative-Nucleoside Transporter 2/genetics/metabolism; *Gene Expression Profiling; Humans; Killer Cells, Natural/drug effects/*metabolism; Membrane Transport Proteins/genetics/metabolism; RNA, Messenger/genetics/metabolism; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes/drug effects/metabolism
Subjects: Cell Types > Blood and Immune Cells > Killer cells
Therapeutics > Transplantation > Stem Cell transplantation
Therapeutics > Drug Therapy
Depositing User: Library Staff
Date Deposited: 23 Sep 2008 19:46
Last Modified: 14 Feb 2012 14:43

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