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

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.