Effects of thymidylate synthase polymorphisms on toxicities associated with high-dose methotrexate in childhood acute ly
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ORIGINAL ARTICLE
Effects of thymidylate synthase polymorphisms on toxicities associated with high‑dose methotrexate in childhood acute lymphoblastic leukemia Abrar Al‑Sheikh1 · Al‑Motassem Yousef1 · Daniah Alshamaseen1 · Rand Farhad1 Received: 15 July 2020 / Accepted: 26 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Background High-dose methotrexate (HD- MTX) is the cornerstone of chemotherapy for acute lymphoblastic leukemia (ALL), and one of its target enzymes is Thymidylate Synthase (TYMS). We hypothesized that genetic polymorphisms of TYMS gene would be associated with MTX toxicity in ALL children. Methods 64 children with ALL were included in this study. Genotyping analysis was conducted on three common polymorphisms: tandem repeats in the promoter-enhancer region (VNTR), 6 bp ins/del (1494del6) in the 5′UTR, and rs2790 A > G in the 3′-untranslated region (3′-UTR). The association between genetic polymorphisms and MTX toxicity was studied. Results Genetic polymorphism of TYMS was associated with hematological toxicities but not with non-hematological adverse events. A significant association between TYMS 1494del6 genotypes and incidence of neutropenia (ANC G genetic polymorphisms and MTX hematologic toxicities. Conclusion Genetic polymorphism of TYMS1494del6 may modulate susceptibility to MTX toxicity. Keywords Acute lymphoblastic leukemia · High-dose methotrexate · Toxicity · Genetic polymorphisms · Thymidylate synthase
Introduction Leukemia is a common type of childhood cancer [1], accounting for 30% of Jordanian pediatrics cancer in 2012 statistics [2]. Treatment of ALL is given in three main phases called: induction, consolidation, and maintenance. One of the drugs that are given in the consolidation phase Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04197-8) contains supplementary material, which is available to authorized users. * Al‑Motassem Yousef [email protected] 1
Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, The University of Jordan, Queen Rania Street, Amman 11942, Jordan
is high-dose methotrexate (HD-MTX) [3]. MTX is antineoplastic, and an antimetabolite drug. It Inhibits thymidylate (dTMP) synthesis by substrate depletion. As MTX act as a competitive inhibitor of dihydrofolate reductase (DHFR) which results in decrease in tetrahydrofolate (THF) levels, thus resulting in attenuated DNA/protein/lipid methylation, and inhibition of thymidylate synthase TYMS [4]. Because of TYMS synthesis inhibition, it interferes with DNA synthesis, repair, and cellular replication and hence inhibits proliferation of cancer cells [5]. MTX does not affect DNA synthesis only, but protein synthesis as well. Production of mRNA is inhibited due to lack of thymine monophosphate; thus, protein synthesis will be inhibited as well [6]. The gene TYMS is located on chromosome 18p11.32 and it is composed of six introns with sizes ranging between 507 and 6271 bp and seven exons with si
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