In vivo mechanisms of resistance to cytarabine in acute myeloid leukaemia.
Factors that reduce the intracellular concentration of triphosphorylated cytarabine (ara-CTP), the active form of cytarabine (ara-C), may induce chemoresistance in acute myeloid leukaemia (AML) patients. These factors include reduced influx of ara-C by the hENT1 transporter, reduced phosphorylation by deoxycytidine kinase (dCK), and increased degradation by high Km cytoplasmic 5'-nucleotidase (5NT) and/or cytidine deaminase (CDD). Increased levels of DNA polymerase alpha (DNA POL) and reduced levels of topoisomerase I (TOPO I) and topoisomerase II (TOPO II) have also been detected in ara-C-resistant cell lines. To determine whether these factors are implicated in clinical ara-C resistance, we analysed the expression of these parameters at diagnosis, using reverse transcription polymerase chain reaction, in the blast cells of 123 AML patients treated with ara-C. At diagnosis, hENT1, dCK, CDD, 5NT, TOPO I, TOPO II, DNA POL and MDR1 were expressed in 83%, 22%, 7%, 37%, 59%, 37%, 39% and 16% of patients respectively. In univariate analysis, patients with expression of 5NT or DNA POL at diagnosis had significantly shorter disease-free survival (DFS). In multivariate analysis, DNA POL positivity and hENT1 deficiency were related to a shorter DFS. In univariate analysis, patients with 5NT-positive blasts had significantly shorter overall survival (OS). In multivariate analysis, shorter OS was related to DNA POL positivity. These results suggest that expression of DNA POL, 5NT and hENT1 at diagnosis may be resistance mechanisms to ara-C in AML patients.
Galmarini
Carlos M
CM
Unité INSERM 453, Laboratoire de Cytologie Analytique, Faculté de Médecine Rockefeller, 8 avenue Rockefeller, 69373 Lyon, France. fgalma@rockefeller.univ-lyon.fr
Thomas
Xavier
X
Calvo
Fabien
F
Rousselot
Philippe
P
Rabilloud
Muriel
M
El Jaffari
Assia
A
Cros
Emeline
E
Dumontet
Charles
C
D015720:5'-Nucleotidase / Q000032:analysis; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis; D003561:Cytarabine / Q000627:therapeutic use*; D003564:Cytidine Deaminase / Q000032:analysis; D004256:DNA Polymerase I / Q000032:analysis; D004264:DNA Topoisomerases, Type I / Q000032:analysis; D004250:DNA Topoisomerases, Type II / Q000032:analysis; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D033721:Equilibrative Nucleoside Transporter 1; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism; D008214:Lymphocytes / Q000737:chemistry; D008297:Male; D026901:Membrane Transport Proteins / Q000032:analysis; D008875:Middle Aged; D015999:Multivariate Analysis; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015415:Biomarkers; D033721:Equilibrative Nucleoside Transporter 1; D007166:Immunosuppressive Agents; D026901:Membrane Transport Proteins; C438649:SLC29A1 protein, human; D003561:Cytarabine; D004256:DNA Polymerase I; D015720:5'-Nucleotidase; D003564:Cytidine Deaminase; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II