Potential mechanisms of resistance to cytarabine in AML patients.
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 alpha (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.
Galmarini
Carlos M
CM
Unité INSERM 453, Laboratoire de Cytologie Analytique, Faculté de Médecine Rockefeller, 8, avenue Rockefeller, 69373 Lyon Cedex 08, France. fgalma@rockefeller.univ-lyon.fr
Thomas
Xavier
X
Calvo
Fabien
F
Rousselot
Philippe
P
El Jafaari
Assia
A
Cros
Emeline
E
Dumontet
Charles
C
D015720:5'-Nucleotidase / Q000235:genetics / Q000502:physiology; D000208:Acute Disease; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D003561:Cytarabine / Q000494:pharmacology* / Q000627:therapeutic use; D003564:Cytidine Deaminase / Q000235:genetics / Q000502:physiology; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000502:physiology; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins; D003842:Deoxycytidine Kinase / Q000235:genetics / Q000502:physiology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology*; D033721:Equilibrative Nucleoside Transporter 1; D005260:Female; D005602:France / Q000453:epidemiology; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D015993:Life Tables; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000502:physiology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D033721:Equilibrative Nucleoside Transporter 1; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; C438649:SLC29A1 protein, human; D003561:Cytarabine; D003842:Deoxycytidine Kinase; D015720:5'-Nucleotidase; D003564:Cytidine Deaminase; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II