Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia

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 metabol...

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Bibliographic Details
Published in:European journal of clinical pharmacology 2012-09, Vol.68 (9), p.1233-1242
Main Authors: Adam de Beaumais, Tiphaine, Jacqz-Aigrain, Evelyne
Format: Article
Language:English
Subjects:
Age Factors
Antimetabolites, Antineoplastic - adverse effects
Antimetabolites, Antineoplastic - pharmacokinetics
Biological and medical sciences
Biomedical and Life Sciences
Biomedicine
Biotransformation - genetics
Child
Drug therapy
Genetics
Genotype
Hematologic and hematopoietic diseases
Humans
Leukemia
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Medical sciences
Mercaptopurine - adverse effects
Mercaptopurine - pharmacokinetics
Pediatrics
Pharmacogenetics
Pharmacology
Pharmacology. Drug treatments
Pharmacology/Toxicology
Phenotype
Polymorphism, Single Nucleotide
Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism
Review Article
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Summary: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. Aim 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.
ISSN:0031-6970
1432-1041
DOI:10.1007/s00228-012-1251-4