Study of Pharmacogenetic factors affecting transport metabolism and regulation of 6 mercaptopurine and methotrexate in childhood acute lymphoblastic leukemia

Abstract

Acute lymphoblastic leukemia is cancer of lymphoid cells it is reported more commonly in pediatric patients between 2 to 5 years of age Combinational drug therapy including 6 mercaptopurine and methotrexate are reported to enhance treatment outcome Around 20 percent of pediatric ALL patients develop treatment related adverse effects during therapy Genetics is among several factors that can alter drug metabolism which can influence the treatment outcome In our study we evaluated 127 pediatric All patients for eleven genetic variants from seven genes using Sanger sequencing PCR RFLP and ARMS PCR Multifactorial dimensionality reduction and multinomial logistic regression analysis was performed for modeling epistasis and to predict the variable relationships respectively Bioinformatics analysis were performed to observe impact of genetic variations on intramolecular and ligand interactions Gene gene interaction analysis was used for identification of other possible markers The frequency of TPMT alleles were found to be rare and the two patients tested positive were presented with multiple episodes of TRAEs Among all the genotypes inspected for 6 MP and MTX associated TRAEs SLC19A1 and NUDT15 showed significant association which was further validated with MDR and regression analysis Difference in tolerated drug dose was found among patients with different genotypes Bioinformatics analysis showed genetic variation in TPMT and NUDT15 to possibly impact inter and intramolecular interactions STRING analysis identified DUT and DHFR to have multiple evidence of protein and protein interactions that can be considered as candidate gene for future studies newline