Association analysis between adverse drug reactions to cytarabine therapy and single nucleotide polymorphisms in cytarabine metabolic genes in patients with hematopoietic tumor

Abstract

Purpose: Cytarabine arabinoside (Ara-C) is an anti-metabolite that is commonly used as a therapeutic agent for acute leukemia; however, it can cause adverse drug reactions, such as digestive disorders, rashes, and fever. Therefore, identification of gene markers that can accurately predict the development of adverse drug reactions is useful for selecting effective drugs for therapy. After entering the cells, Ara-C is metabolized to Ara-C triphosphate, which inhibits DNA synthesis and exhibits antitumor activity. Therefore, we conducted an association study between the adverse reactions to cytarabine therapy and single nucleotide polymorphisms (SNPs) in cytarabine metabolic genes. Methods: Among the patients treated with cytarabine at the Department of Hematology at Tokushima University Hospital, 46 patients provided informed consent and were included in this study. We selected 14 tag SNPs located in nine genes that are involved in the cytarabine metabolic pathway; these SNPs were genotyped using the polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) technique. Association analyses between adverse reactions to AraC therapy and SNPs were performed using logistic regression analysis. Results: The rs9394992 polymorphism in the SLC29A1 gene and rs3886768 polymorphism in the DCTD gene were associated with the development of rash after Ara-C therapy. The rs7277 polymorphism in the DCTD gene was associated with fever, and the rs16945930 polymorphism in the ABCC11 gene was associated with sore throat. Conclusions: Our findings suggest that SNPs in the Ara-C metabolic genes influence the development of adverse reactions to Ara-C, and the results suggest that these genes can be predictive of adverse reactions to Ara-C therapy.