The T_T genotype within the NME1 promoter single nucleotide polymorphism -835 C/T is associated with an increased risk of cytarabine induced neurotoxicity in patients with acute myeloid leukemia

Leuk Lymphoma. 2012 May;53(5):952-7. doi: 10.3109/10428194.2011.635862. Epub 2011 Dec 7.

Abstract

Recently, numerous studies have been published on inter-individual variations in the response to specific treatment with cytostatic agents such as cytarabine (Ara-C) in patients with acute myeloid leukemia (AML). Differences at the genetic level and potentially associated changes in the expression and/or function of specific drug metabolizing enzymes appear to play an important role in this inter-individual susceptibility. Single nucleotide polymorphisms (SNPs) can be easily assessed in order to further investigate and explain inter-individual differences as to Ara-C associated toxicity and response to treatment. In this retrospective study we correlated five SNPs within the NME1 promoter with drug-induced toxicity, disease-free survival and overall survival (OS) in 360 Caucasian patients suffering from AML. A significant correlation between SNPs and disease-free survival or overall survival was not found. For the NME1 promoter SNP - 835 C/T (rs2302254) we identified a significant correlation between low platelet counts and better Eastern Cooperative Oncology Group performance status (grade 3/4). An increased risk of neurotoxicity was identified for the NME1 promoter SNP - 835 C/T (rs2302254) genotype T_T. Multivariate analyses also showed that these variables were independent risk factors. Ara-C causes neuronal cell death by introduction of apoptosis with reactive oxygen species, causing oxidative DNA damage and initiating the p53-dependent apoptotic program. Recent data show that oral administration of the antioxidant N-acetylcysteine for 14 days is able to prevent Ara-C induced behavioral deficits and cellular alterations of the adult cerebellum in a rat model.

Publication types

  • Controlled Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / therapeutic use
  • Adolescent
  • Adult
  • Aged
  • Apoptosis
  • Cytarabine / adverse effects*
  • Female
  • Genotype
  • Humans
  • Leukemia, Myeloid, Acute / complications*
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics*
  • Male
  • Middle Aged
  • NM23 Nucleoside Diphosphate Kinases / genetics*
  • Neurons / pathology
  • Neurotoxicity Syndromes / etiology*
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic*
  • Retrospective Studies
  • Survival Rate
  • Young Adult

Substances

  • NM23 Nucleoside Diphosphate Kinases
  • Cytarabine
  • NME1 protein, human
  • Acetylcysteine