title: [New techniques for optimization of thiopurine therapy in leukemia and transplantation].
abstract: BACKGROUND
  The majority of chemotherapeutic agents are administered at fixed doses that are close to those maximally tolerated.
  
  
  METHODS
  This review is based on current knowledge about the metabolism of thiopurines and the clinical implications of genetic polymorphism in thiopurine-S-methyltransferase (TPMT).
  
  
  RESULTS
  Intracellularly thiopurines, e.g. 6-MP, are anabolized to cytotoxic 6-thioguanine nucleotides (6-TGN) that are incorporated into DNA and RNA. A competing pathway is S-methylation of 6-MP and its initial nucleotide metabolites by TPMT. In childhood acute lymphocytic leukaemia, high erythrocyte concentrations of 6-TGN correlate with the degree of leukopenia and a good prognosis, while low concentrations appear to be associated with higher risk of relapse. In most populations studied, approximately 10% have intermediate TPMT activity and 1/300 lacks TPMT activity due to one or two mutant TPMT alleles, respectively.
  
  
  CONCLUSIONS
  Phenotyping or genotyping may be used to identify patients as deficient or intermediate thiopurine metabolizers. This suggests that they should receive a profound or moderate reduction in dosage to avoid haematopoietic toxicity.
authors.affiliation: Avdeling for farmakologi Institutt for farmasi, Universitetet i Tromsø 9037 Troms. thrinal@farmasi.uit.no
authors.forename: Thrina
authors.initials: T
authors.lastname: Loennechen
authors.forename: Roy Andre
authors.initials: RA
authors.lastname: Lysaa
authors.forename: Trude
authors.initials: T
authors.lastname: Giverhaug
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
authors.forename: Lars-Eirik
authors.initials: LE
authors.lastname: Mathiesen
authors.forename: Jarle
authors.initials: J
authors.lastname: Aarbakke
mesh_terms: D000328:Adult; D000963:Antimetabolites / Q000008:administration & dosage* / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000378:metabolism; D002648:Child; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000378:metabolism; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D016377:Organ Transplantation; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011687:Purines / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D000963:Antimetabolites; D000964:Antimetabolites, Antineoplastic; D007166:Immunosuppressive Agents; D011687:Purines; D008780:Methyltransferases