Host thiopurine methyltransferase status affects mercaptopurine antileukemic effectiveness in a murine model.
Pharmacogenet Genomics
; 24(5): 263-71, 2014 May.
Article
en En
| MEDLINE
| ID: mdl-24710003
ABSTRACT
BACKGROUND:
Thiopurines are used for many cancers, including acute lymphoblastic leukemia (ALL). Patients with an inherited host defect in thiopurine methyltransferase (TPMT) are at high risk for life-threatening toxicity if treated with conventional dosages, but the impact on antileukemic efficacy is less clear. MATERIALS ANDMETHODS:
We treated thiopurine-sensitive BCR-ABL+Arf-null Tpmt+/+ ALL in Tpmt+/+, +/-, or -/- recipient mice to test the impact of the host polymorphism on antileukemic efficacy.RESULTS:
Median survival was similar in untreated mice of different Tpmt genotypes (16-18 days). However, in mice treated with low-dose mercaptopurine (such as tolerated by TPMT-/- patients), the difference in 30-day leukemia-free survival by Tpmt genotype was profound 5% (±9%) for Tpmt+/+ mice, 47% (±26%) for Tpmt+/- mice, and 85% (±14%) for Tpmt-/- mice (P=5×10), indicating a substantial impact of host Tpmt status on thiopurine effectiveness. Among Tpmt+/+ recipient mice, leukemia-free survival improved with higher doses of mercaptopurine (similar to doses tolerated by wild-type patients) compared with lower doses, and at higher doses was comparable (P=0.6) to the survival of Tpmt-/- mice treated with the lower dose.CONCLUSIONS:
These findings support the notion that germline polymorphisms in Tpmt affect not only host tissue toxicity but also antitumor effectiveness.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Leucemia-Linfoma Linfoblástico de Células Precursoras
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Mercaptopurina
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Metiltransferasas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Pharmacogenet Genomics
Asunto de la revista:
FARMACOLOGIA
/
GENETICA MEDICA
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos