الفهرس 
Acknoweldgment
Acute lymphoblastic leukemiaOnly 14 pages are availabe for public view
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Abstract
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer (nearly one third of all childhood cancers). The prognosis for ALL has improved owing to the development and proper usage of multiple chemotherapeutic drugs that lead to a survival of about 80%.
6-mercaptopurine (6-MP) is one of the backbone drugs used for maintenance therapy in ALL. It is a prodrug devoid of intrinsic activity and needs activation inside the cells through multi-enzymatic reactions to 6-thio-guanine nucleotides (6-TGNs), which participate in the anti-leukemic effect of 6-MP through incorporation in the DNA of leukemic cells. The different metabolites of 6-MP can also contribute to toxicity. ALL relapse and hematological toxicity are major clinical problems in patients maintained on 6-MP treatment and both can be fatal.
The activity of the enzymes thiopurine-S-methyl transferase (TPMT) and inosine triphosphate pyrophosphatase (ITPase), which are involved in the metabolic pathways of thiopurine drugs like 6-MP and azathioprine (AZA), presents wide inter-individual variability, partly due to genetic polymorphisms.
Some patients from different ethnic groups treated with thiopurine drugs had showed an increased risk of hematological toxicity and other forms of adverse drug reactions if they carried at least one of the TPMT or ITPA SNPs. Therefore, genotype-based dose adjustment of these drugs may improve patient outcome.
Several others enzymes or transporters are involved in 6-MP pathway: inosine 5´-monophosphate dehydrogenase 1 (IMPDH1) catalyzes the conversion of 6-thioinosine monophosphate (6-TIMP) into 6-thioxanthosine monophosphate (6-TXMP), which in turn leads to the formation of 6-TGNs. Solute carriers (SLC) 28A2, 28A3, 29A1 and 29A2 are involved in 6-MP uptake, and ATP-binding cassette (ABCC4 and ABCC5) transporters are involved in the efflux of 6-MP active metabolites. ABCC4 is also involved in the efflux of 6-MP itself. Little data is available regarding the impact of SNPs in these important proteins on 6-MP outcomes.
The aim of the present study was to identify genetic factors associated with both hematological toxicity (i.e. neutropenia, agranulocytosis and/or leucopenia) and therapeutic failure (i.e. ALL relapse) in patients with ALL maintained on 6-MP in Upper (Southern) Egypt. Important pharmacogenes involved in the 6-MP activation and elimination pathways (including TPMT and ITPA) had been considered and candidate polymorphisms had been carefully selected based on the literature.
Our study had showed there was a significant association between hematological toxicity and selected SNPs in genes coding for proteins involved in the processes of influx/efflux and activation/deactivation of 6-MP and its metabolites in ALL patients. These transporter proteins and enzymes play an important role in the balance between different thiopurine metabolites that contribute to response and cellular toxicity, hence, genetic polymorphisms could affect the functions of these important proteins, leading to either diminished efficacy or increased toxicity.
We have focused on the major hematological toxicity that may occur in the bone marrow of thiopurine receivers specially 6-MP used in ALL patients because this drug is used as long maintenance treatment (2-3 years). selection of the SNPs was based on their frequencies, functions or their previously reported contribution in clinical outcomes of drug treatment. The ITPA SNP rs7270101 had been associated with the risks of both neutropenia and leucopenia; Females were at higher risk of leucopenia and need strict follow up.
We reported significant associations for SNPs in the SLC and ABC transporters. Further studies on the concentrations of thiopurine metabolites like 6-TGNs, 6-TITP and 6-MTITP as well as ratios between them are needed to confirm, support and clarify the mechanisms of these associations. Thiopurine pharmacogenetics is complex, the distributions of related SNPs vary among different ethnic groups, so that dose individualization based on new pharmacogenetic biomarkers may be useful in the future to improve thiopurine therapeutic outcome. Patients with ALL and IBD receiving thiopurines should be evaluated for SNPs highlighted in our study to predict the efficacy/toxicity potential in each patient.