[New techniques for optimization of thiopurine therapy in leukemia and transplantation].
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.
Loennechen
Thrina
T
Avdeling for farmakologi Institutt for farmasi, Universitetet i Tromsø 9037 Troms. thrinal@farmasi.uit.no
Lysaa
Roy Andre
RA
Giverhaug
Trude
T
Sylte
Ingebrigt
I
Mathiesen
Lars-Eirik
LE
Aarbakke
Jarle
J
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
D000963:Antimetabolites; D000964:Antimetabolites, Antineoplastic; D007166:Immunosuppressive Agents; D011687:Purines; D008780:Methyltransferases