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[New techniques for optimization of thiopurine therapy in leukemia and transplantation]
Thrina Loennechen1, Roy Andre Lysaa, Trude Giverhaug
1Avdeling for farmakologi Institutt for farmasi, Universitetet i Tromsø 9037 Troms. thrinal@farmasi.uit.no
Background:
The majority of chemotherapeutic agents are administered at fixed doses that are close to those maximally tolerated.
Material And 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.
Interpretation:
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.