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Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia

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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.

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.

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Abbreviations

6-dTGTP:

6- deoxy thioguanosine triphosphate

6-MeMP:

6-methylmercaptopurine

6-meTIDP:

6-methyl-thioinosine diphosphate

6-meTIMP:

6-methyl-thioinosine monophosphate

6-meTITP:

6-methyl-thioinosine triphosphate

6-MMPN:

6-methyl mercaptopurine nucleotides

6-MP:

6-mercaptopurine

6-TGDP:

6-thioguanine diphosphate

6-TGMP:

6-thioguanosine monophosphate

6-TGN:

6-thioguanine nucleotides

6-TGTP:

6-thioguanosine triphosphate

6-TIDP:

6-thioinosine diphosphate

6-TIMP:

6-thioinosine monophosphate

6-TITP:

6-thioinosine triphosphate

6-TXMP:

6-thioxanthine monophosphate

ABC:

ATP-binding cassette

ALL:

Acute lymphoblastic leukemia

AZA:

Azathioprine

DNA:

Deoxyribonucleic acid

GMPS:

Guanosine monophosphate synthetase

HGPRT:

Hypoxanthine guanine phosphoribosyltransferase

IBD:

Inflammatory bowel disease

IMPDH:

Inosine monophosphate dehydrogenase

ITPA:

Inosine triphosphate pyrophosphatase

MTHFR:

5,10-Methylenetetrahydrofolate reductase

MRP:

Multidrug resistance associated protein

NE:

Not explored

Pmol:

Picomoles

PRPP:

Phosphoribosylpyrophosphate

RBC:

Red blood cells

SAM:

S-adenosylmethionine

SLC:

Solute carrier family

SNPs:

Single nucleotide polymorphisms

TPMT:

Thiopurine S-methyl transferase

TUA:

Thiouric acid

XMP:

Xanthosine monophosphate

XO:

Xanthine oxidase

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Adam de Beaumais, T., Jacqz-Aigrain, E. Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia. Eur J Clin Pharmacol 68, 1233–1242 (2012). https://doi.org/10.1007/s00228-012-1251-4

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