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Potential mechanisms of resistance to cytarabine in AML patients

Carlos M Galmarini1, Xavier Thomas, Fabien Calvo

  • 1Unité INSERM 453, Laboratoire de Cytologie Analytique, Faculté de Médecine Rockefeller, 8, avenue Rockefeller, 69373 Lyon Cedex 08, France. fgalma@rockefeller.univ-lyon.fr

Leukemia Research
|May 15, 2002
PubMed

Insights

Cytarabine (ara-C) resistance in acute myeloid leukemia (AML) may be linked to specific gene expressions. High cytoplasmic 5-nucleotidase (5NT) and low human equilibrative nucleoside transporter 1 (hENT1) expression in leukemia cells at diagnosis correlate with poorer patient survival.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Hematology

Background:

  • Cytarabine (ara-C) is a key chemotherapy agent for acute myeloid leukemia (AML).
  • Mechanisms of ara-C resistance in AML are not fully understood.
  • Several nucleoside transporters and metabolizing enzymes may influence ara-C efficacy.

Purpose of the Study:

  • To investigate the role of 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) in clinical ara-C resistance in AML.
  • To correlate the expression levels of these molecules with patient outcomes.

Main Methods:

  • Analysis of gene expression in blast cells from 77 AML patients using reverse transcriptase polymerase chain reaction (rt-PCR).
  • Samples were collected at diagnosis and for 31 patients at first relapse.
  • Univariate and multivariate analyses were performed to assess correlations with survival.

Main Results:

  • Patients with high 5NT expression or deficient hENT1 expression at diagnosis showed significantly shorter disease-free survival (DFS).
  • These patients also had significantly shorter overall survival (OS).
  • Expression levels of dCK, CDD, TOPO I, and TOPO II were not significantly correlated with DFS or OS.

Conclusions:

  • Expression of 5NT and reduced hENT1 in leukemic blasts at diagnosis are correlated with clinical outcomes in AML patients treated with ara-C.
  • These factors may contribute to resistance mechanisms against ara-C in AML.
  • Targeting or monitoring 5NT and hENT1 could potentially improve AML treatment strategies.

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