The human equilibrative nucleoside transporter I mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia

I. Hubeek*, R. W. Stam, G. J. Peters, R. Broekhuizen, J. P.P. Meijerink, E. R. Van Wering, B. E.S. Gibson, U. Creutzig, C. M. Zwaan, J. Cloos, D. J. Kuik, R. Pieters, G. J.L. Kaspers

*Corresponding author for this work

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Abstract

Cytarabine (ara-C) is the most effective agent for the treatment of acute myeloid leukaemia (AML). Aberrant expression of enzymes involved in the transport/metabolism of ara-C could explain drug resistance. We determined mRNA expression of these factors using quantitative-real-time-PCR in leukemic blasts from children diagnosed with de novo AML. Expression of the inactivating enzyme pyrimidine nucleotidase-1 (PN-1) was 1.8-fold lower in FAB-M5 as compared to FAB-M1/2 (P = 0.007). In vitro sensitivity to deoxynucleoside analogues was determined using the MTT-assay. Human equilibrative nucleoside transporter-1 (hENT1) mRNA expression and ara-C sensitivity were significantly correlated (rp = -0.46; P = 0.001), with three-fold lower hENT1 mRNA levels in resistant patients (P = 0.003). hENT1 mRNA expression also seemed to correlate inversely with the LC50 values of cladribine (rp = -0.30; P = 0.04), decitabine (rp = -0.29; P = 0.04) and gemcitabine (r p = -0.33; P = 0.02). Deoxycytidine kinase (dCK) and cytidine deaminase (CDA) mRNA expression seemed to correlate with in vitro sensitivity to gemcitabine (rp = -0.31; P = 0.03) and decitabine (rp = 0.33; P = 0.03), respectively. The dCK/PN-1 ratio correlated inversely with LC50 values for gemcitabine (rp = -0.45, P = 0.001) and the dCK/CDA ratio seemed to correlate with LC50 values for decitabine (rp = -0.29; 0.04). In conclusion, decreased expression of hENT1, which transports ara-C across the cell membrane, appears to be a major factor in ara-C resistance in childhood AML.

Original languageEnglish
Pages (from-to)1388-1394
Number of pages7
JournalBritish Journal of Cancer
Volume93
Issue number12
DOIs
Publication statusPublished - 12 Dec 2005

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