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Mechanisms of resistance to decitabine in the myelodysplastic syndrome

Taichun Qin1, Ryan Castoro, Samih El Ahdab

  • 1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

Plos One
|August 23, 2011
PubMed
Abstract

Insights

Primary resistance to 5-aza-2'-deoxycytidine (DAC) in myelodysplastic syndromes (MDS) involves pharmacological mechanisms. Hypomethylation does not prevent relapse in patients undergoing DAC treatment.

Area of Science:

  • Hematology
  • Cancer Biology
  • Epigenetics

Background:

  • 5-aza-2'-deoxycytidine (DAC) is a DNA methylation inhibitor used to treat myelodysplastic syndromes (MDS).
  • Acquired resistance to DAC limits its therapeutic efficacy in MDS.
  • Mechanisms underlying primary and secondary DAC resistance in MDS are not fully understood.

Purpose of the Study:

  • To investigate the mechanisms of primary and secondary resistance to DAC in patients with MDS.
  • To identify potential biomarkers for predicting DAC response and resistance.

Main Methods:

  • Quantitative Real-Time PCR was used to analyze DAC metabolism gene expression in MDS patients.
  • Bisulfite pyrosequencing and Methylated CpG Island Amplification Microarray (MCAM) were employed for quantitative methylation analysis.
  • Analysis included 32 responders and non-responders, and 14 patients with secondary resistance.

Main Results:

  • A higher cytidine deaminase/deoxycytidine kinase (CDA/DCK) ratio was observed in primary non-responders, suggesting a role in primary resistance.
  • No significant differences in DAC metabolism genes or DCK mutations were found at relapse.
  • Global hypomethylation was observed at relapse compared to diagnosis, with decreased methylation in specific genes.

Conclusions:

  • Pharmacological mechanisms, such as altered gene expression related to DAC metabolism, contribute to primary resistance.
  • While global hypomethylation occurs during DAC treatment, it does not appear to prevent relapse in MDS patients.

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