Fludarabine uptake mechanisms in B-cell chronic lymphocytic leukemia.
Nucleoside derivatives are currently used in the treatment of hematologic malignancies. Although intracellular events involved in the pharmacologic action of these compounds have been extensively studied, the role of plasma membrane transporters in nucleoside-derived drug bioavailability and action in leukemia cells has not been comprehensively addressed. We have monitored the amounts of mRNA for the 5 nucleoside transporter isoforms cloned so far (CNT1, CNT2, CNT3, ENT1, and ENT2) in several human cell types and in normal human leukocytes. We then examined the expression patterns of these plasma membrane proteins in patients with chronic lymphocytic leukemia (CLL) and correlated them with in vitro fludarabine cytotoxicity. Despite a huge individual variability in the mRNA amounts for every transporter gene expressed in CLL cells (CNT2, CNT3, ENT1, and ENT2), no relationship between mRNA levels and in vitro fludarabine cytotoxicity was observed. Fludarabine accumulation in CLL cells was mostly, if not exclusively, mediated by ENT-type transporters whose biologic activity was clearly correlated with fludarabine cytotoxicity, which reveals a role of ENT-mediated uptake in drug responsiveness in patients with CLL.
Molina-Arcas
Míriam
M
Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain.
Bellosillo
Beatriz
B
Casado
F Javier
FJ
Montserrat
Emili
E
Gil
Joan
J
Colomer
Dolors
D
Pastor-Anglada
Marçal
M
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008558:Melphalan / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; C121321:ENT2 protein, S cerevisiae; D033721:Equilibrative Nucleoside Transporter 1; D007074:Immunoglobulin G; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; C438649:SLC29A1 protein, human; D029701:Saccharomyces cerevisiae Proteins; C051713:antineoplastic agent K 18; C065171:cif nucleoside transporter; D014740:Vidarabine; C024352:fludarabine; D008558:Melphalan