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Pharmacogenomics of Thiopurine-Induced Toxicity in Children

  • Hina SalahuddinEmail author
  • Muhammad Junaid Iqbal Tahir
Chapter
  • 112 Downloads

Abstract

Thiopurine drugs play an important role in the treatment of acute lymphoblastic leukemia by inhibiting the proliferation of cell. It is done by blocking various pathways of nucleic acid synthesis. Because of this typical property of these drugs, they are used in cancer treatment. Mercaptopurine (6-MP) and thioguanine (6-TG) act synergistically in inhibiting the synthesis of purine, ultimately inhibiting DNA synthesis. Incorporation of 6-TGN (thioguanine nucleotides) into DNA is responsible for anticancer activity of thiopurine drugs. Two-thirds of children suffering from acute lymphoblastic leukemia (ALL) can be cured by using 6-MP. Thiopurine drugs concentration in the body is regulated by an enzyme called thiopurine S-methyltransferase (TPMT). Studies on red blood cells suggest that TPMT activity is trimodal in its distribution. Ninety percent of individuals possess normal TPMT activity, but in the remaining 10% of individuals, low TPMT activity is observed. This is because of presence of genetic polymorphism in TPMT gene. Metabolism of thiopurine drugs in our body depends upon the genetic variant of TPMT gene we possess. Before initiating thiopurine drug therapy, it is necessary to determine TPMT status of the patient. Usually TPMT genotyping is used for this purpose. Standard dose of thiopurine drugs is used for patients with high TPMT enzyme activity. In patients, exhibiting low TPMT activity dosage of thiopurine drugs is reduced, or an alternate therapy is considered to avoid adverse drug reactions like myelosuppression, hematologic toxicity, and hypoplasia of the bone marrow.

Keywords

Acute lymphoblastic leukemia Azathioprine Mercaptopurine Thioguanine Thioguanine nucleotide Thiopurine S-methyltransferase TPMT haplotype Myelosuppression Hematologic toxicity Hypoplasia of the bone marrow 

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Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • Hina Salahuddin
    • 1
    Email author
  • Muhammad Junaid Iqbal Tahir
    • 1
  1. 1.University of OkaraOkaraPakistan

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