title: Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia.
abstract: BACKGROUND
  The backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabolites are represented by 6-thioguanine nucleotides (6-TGN) and methylated metabolites primarily methylated by the thiopurine S-methyltransferase enzyme (TPMT). The genetic polymorphism affecting TPMT activity displays an important inter-subject variability in metabolites pharmacokinetics and influences the balance between 6-MP efficacy and toxicity: patients with high 6-TGN levels are at risk of myelosuppression while patients with high levels of methylated derivates are at hepatotoxic risk. However, the genetic TPMT polymorphism does not explain all 6-MP adverse events and some severe toxicities leading to life-threatening conditions remain unexplained. Additional single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in 6-MP metabolism and 6-MP transporters may also be responsible for this inter-individual 6-MP response variability.
  
  
  OBJECTIVE
  This review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL.
authors.affiliation: Department of Pediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, 48 Boulevard Sérurier, 75019 Paris, France. tiphaine.debeaumais@rdb.aphp.fr
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Adam de Beaumais
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jacqz-Aigrain
mesh_terms: D000367:Age Factors; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics*; D001711:Biotransformation / Q000235:genetics; D002648:Child; D005838:Genotype; D006801:Humans; D015122:Mercaptopurine / Q000009:adverse effects / Q000493:pharmacokinetics*; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine