Genetic polymorphism in MDR1 C3435T is adeterminant of methotrexate cerebrospinal fluid concentrations in Chinese children with acute lymphoblastic leukemia .

Abstract

This study aimed to investigate the influence of single-nucleotide polymorphism in exon 26 (C3435T) of multidrug resistance 1 (MDR1) transporter gene on the concentration of methotrexate (MTX) in Chinese childhood patients with acute lymphoblastic leukemia (ALL) receiving intravenous (IV) and intrathecal (IT) high-dose methotrexate (HDMTX) chemotherapy. MDR1 C3435T polymorphism was investigated in 60 patients with Chinese childhood ALL. The study also compared the MDR1; polymorphism between the patients with Chinese childhood ALL and the published data on Americans, Mexicans, Caucasians, and Thais. The C3435T polymorphism was identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequence analysis. Cerebrospinal fluid (CSF) and plasma concentrations of MTX were measured using high-performance liquid chromatography (HPLC). MTX concentrations were compared according to MDR1 C3435T genotypes. The frequencies of MDR1 C3435T genotype in male and female patients with Chinese childhood ALL were significantly different (p = 0.001). For the frequencies of MDR1 C3435T genotype in Hui and Han patients with Chinese childhood ALL there was no difference (p = 0.188). The distribution of allele frequencies in patients with Chinese childhood ALL was similar to the published data on Americans, Mexican, Caucasians, and Thais (p > 0.05). The CSF concentrations of MTX were found to be significantly different between the C allele (CC + CT) carriers and TT homozygous group (p = 0.04). The plasma concentrations of MTX had no significant difference between the C allele (CC + CT) carriers and TT homozygous group (p > 0.1). This study showed that the polymorphism of MDR1 C3435T influenced the CSF concentration of MTX in patients with Chinese childhood ALL receiving IV and IT HDMTX treatment.