Analysis ofThiopurineS-Methyltransferase Genotype in Children with Acute Lymphoblastic Leukemia by Strip Hybridization
Journal Title: Journal of Medical Science And clinical Research - Year 2014, Vol 2, Issue 7
Abstract
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. The thiopurines, 6- mercaptopurine (6MP) and thioguanine (TG), are the backbone of current therapy for childhood ALL. Since their introduction to leukemia treatment in the 1950s, they have played an essential role in treatment protocols for ALL. ThiopurineS-methyltransferase (TPMT) polymorphism represents a determinant of 6-MP response and ALL outcome and is wellcharacterized in most populations. Four common polymorphic alleles areassociated with impaired activity of the enzyme. These are TPMT*2 (238G>C), TPMT*3A (460G>A, 719A>G), TPMT*3B (460G>A) and TPMT*3C (719A>G). Objective: The aim of the present study was to determine the frequency of the functional TPMT polymorphisms and their association with the occurrence of adverse events, in pediatric patients with standard risk ALL who are subjected to 6-Mercatopurine therapy for consolidation. Patients and Methods: TPMT polymorphism was analyzed in 40 children diagnosed with acute lymphoblastic leukemia and 40 age and sex matched healthy controls.The frequency of TPMT genotypes was examined by PXG-TPMT StripAssay based on Polymerase Chain Reaction (PCR) and reverse hybridizationusing blood samples. Clinical follow up using complete blood picture and liver Dalal Mohammed Nasr Eldin El-Kaffash et al JMSCR Volume 2 Issue 7 July 2014 Page 1741 JMSCR Volume||2||Issue||7||Page1740-1750||July 2014 2014 INTRODUCTION Pediatric ALL is one of the great success stories of modern cancer therapy, with contemporary treatment protocols achieving overall long-term event-free survival rate approaching 94%.(1)The thiopurines, 6-mercaptopurine (6MP) and thioguanine (TG), are the backbone of current therapy for childhood ALL. Since their introduction to leukemia treatment in the 1950s, they have played an essential role in treatment protocols for ALL. Several contemporary treatment protocols for childhood ALL apply consecutive cycles of either 6- mercaptopurine or thioguanine starting as early as during induction consolidation treatment and continue administration during maintenance therapy for up to 36 months after diagnosis.(2) As pro-drugs, thiopurines require bioactivation by a multistep pathway to form thioguanine nucleotides, which are thought to be the major cytotoxic compounds through triggering cell cycle arrest and apoptosis. This process is in competition with direct inactivation of thiopurines or their metabolites by thiopurine S-methyltransferase (TPMT).(2,3) TPMT is a cytosolic enzyme ubiquitously expressed in the human body and catalyzes the S-methylation of thiopurine drugs.(2) TPMT activity exhibits genetic polymorphisms in all large ethnic groups studied to date, including Caucasians, Africans, African- Americans, and Asians. These polymorphisms, which are inherited in an autosomal recessive trait, show a trimodal distribution in a Caucasian population resulting in 89% high, 11% transaminases following 6-MP therapy for consolidation were then performed for patients in order to access drug toxicity. Results:In the study sample, none had homozygous mutant TPMT genotypes (e.g. TPMT*3A/*3A, TPMT*2/*2, TPMT*3A/3C, etc.). Also neither the cases nor the controls in the study sample had TPMT*1/*2 and TPMT*1/*3B genotypes. In patients group, 39 (97.5%) were of the wild-type homozygous TPMT*1/*1 genotype, 1 (2.5%) patient only was of the heterozygous TPMT*1/*3A genotype and no patient had TPMT*1/*3C genotype. In the control group, we identified 36 subjects (90%) with wild-type homozygous TPMT*1/*1 genotype, 3 (7.5%) with heterozygous TPMT*1/*3A genotype and 1 (2.5%) heterozygous TPMT*1/*3C genotype. TPMT*3A was the most prevalent variant allele followed by TPMT*3C detected in the studied sample with an allelic frequency of 2.5% and 0.6%, respectively.The only patient with variant TPMT*1/*3A genotype did not show any evidence of thiopurine intolerance (hematotoxicity and hepatotoxicity). Conclusions: Cases of myelosuppression in ALL pediatric patients treated with 6-MP cannot be all explained by the existence of TPMT alleles (*2, *3A, *3B and *3C). Other polymorphic alleles in TPMT gene or factors other than TPMT polymorphisms may be responsible for the development of toxicity.
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Dalal Mohammed Nasr Eldin El-Kaffash
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