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Prepublished online as a Blood First Edition Paper on October 31, 2002; DOI 10.1182/blood-2002-07-2236.
Submitted July 25, 2002
Accepted October 17, 2002
Fludarabine uptake mechanisms in B-cell chronic lymphocytic leukemia
Miriam Molina-Arcas, Beatriz Bellosillo, F Javier Casado, Emili Montserrat, Joan Gil, Dolors Colomer, and Marcal Pastor-Anglada*
Bioquimica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain
Unitat d'Hematopatologia, Hospital Clinic-IDIBAPS, Barcelona, Spain
Ciencies Fisiologiques II, Campus de Bellvitge, Universitat de Barcelona, Hospitalet, Spain
* Corresponding author; email: mpastor{at}bio.ub.es.
Nucleoside-derivatives are currently used in the treatment of hematological malignancies. Although intracellular events involved in the pharmacological 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 five 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 CLL patients 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. Indeed, fludarabine accumulation in CLL cells was mostly, if not exclusively, mediated by ENT-type transporters whose biological activity was clearly correlated with fludarabine cytotoxicity, which reveals a role of ENT-mediated uptake in drug responsiveness in CLL patients.
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