The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia.
Pharmacogenet Genomics
; 27(6): 236-239, 2017 06.
Article
en En
| MEDLINE
| ID: mdl-28445187
ABSTRACT
Thiopurines [e.g. mercaptopurine (MP)] are widely used as chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia with dose-limiting hematopoietic toxicity. Recently, germline variants in NUDT15 have been identified as a major genetic cause for MP-related bone marrow suppression, and there is increasing interest in the clinical implementation of NUDT15 genotype-guided MP dose individualization. Therefore, we sought to evaluate the effects of NUDT15 on thiopurine metabolism and identify pharmacologic markers to inform NUDT15 genotype-guided MP dosing. In 55 Japanese children with acute lymphoblastic leukemia, we simultaneously measured both thioguanine nucleotides (TGN) in red blood cells and DNA-incorporated thioguanine (DNA-TG) in white blood cells. TGN levels were significantly lower in patients with NUDT15 deficiency, likely because of toxicity-related MP dose reduction. In contrast, when exposed to the same dose of MP, DNA-TG accumulated more efficiently in vivo with increasing number of risk alleles in NUDT15 (P=4.0×10). Cytosolic TGN and nuclear DNA-TG were correlated positively with each other across genotype groups (P=6.5×10), but the ratio of DNA-TG to TGN was significantly higher in NUDT15-deficient patients (P=3.6×10), consistent with excessive MP activation. In conclusion, our results suggest that DNA-TG is a more relevant MP metabolite than TGN to inform NUDT15 genotype-guided dose adjustments.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Purinas
/
Pirofosfatasas
/
Polimorfismo de Nucleótido Simple
/
Leucemia-Linfoma Linfoblástico de Células Precursoras
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Adolescent
/
Child
/
Child, preschool
/
Female
/
Humans
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Infant
/
Male
País/Región como asunto:
Asia
Idioma:
En
Revista:
Pharmacogenet Genomics
Asunto de la revista:
FARMACOLOGIA
/
GENETICA MEDICA
Año:
2017
Tipo del documento:
Article