Potential mechanisms of resistance to cytarabine in AML patients

Abstract 

To determine whether the human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (dCK), cytoplasmic 5′-nucleotidase (5NT), cytidine deaminase (CDD), topoisomerase I (TOPO I) and topoisomerase II α (TOPO II) are involved in clinical resistance to cytarabine (ara-C), we analyzed the level of expression of these parameters by reverse transcriptase polymerase chain reaction (rt-PCR), at diagnosis in the blast cells of 77 acute myeloid leukemia (AML) patients treated with ara-C, including 31 for whom samples were collected at first relapse. By univariate and/or multivariate analyses, patients with expression of 5NT or hENT1 deficiency at diagnosis had significantly shorter disease-free survival (DFS) and overall survival (OS). These results suggest that expression of 5NT and reduced hENT1 in leukemic blasts at diagnosis are correlated with clinical outcome and may play a role in resistance mechanisms to ara-C in patients with AML.

Abbreviations: ALL, acute lymphocytic leukemia, AML, acute myeloid leukemia, ara-C, cytarabine, BM, bone marrow, CDD, cytidine deaminase, CLL, chronic lymphocytic leukemia, CML, chronic myelogenous leukemia, CR, complete response, dCK, deoxycytidine kinase, DFS, disease-free survival, HCL, hairy-cell leukemia, hENT1, human equilibrative nucleoside transporter 1, IC95, 95% confidence interval, LRP, lung resistance-related protein, MDR, multidrug resistance phenotype, MRP, multidrug resistance-associated protein, 5NT, 5′-nucleotidase, OS, overall survival, PB, peripheral blood, P-gp, P-glycoprotein, rs, Spearman’s rank order correlation coefficient, rt-PCR, reverse transcriptase polymerase chain reaction, TOPO I, topoisomerase I, TOPO II, topoisomerase II α, WBC, white-blood count

Keywords: Drug resistance, Cytarabine, 5′-Nucleotidase, Acute myeloid leukemia, Antineoplastic agents, Antimetabolites