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Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia

The Pharmacogenomics Journal volume 15, pages 380–384 (2015)Cite this article

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Abstract

Multidrug resistance protein 4 (MRP4) is involved in the efflux of nucleoside derivatives and has a role in the determination of drug sensitivity. We investigated the relationship between MRP4 genetic polymorphisms and doses of the 6-mercaptopurine (6-MP) and methotrexate. Further, we evaluated the frequency of therapeutic interruption during maintenance therapy in Japanese children with acute lymphoblastic leukemia (ALL). Ninety-four patients received an initial 6-MP dose in the range of 30−50 mg m−2 in this analysis. Patients with homozygous variant allele in any of MRP4 G2269A, C912A and G559T required high frequency of 6-MP dose reduction compared with non-homozygous individuals. Average 6-MP dose for patients with homozygous variant allele on either MRP4 or inosine triphosphate pyrophosphatase was significantly lower than that for patients with non-homozygous variant allele during maintenance therapy (30.5 versus 40.0 mg m−2, P=0.024). Therefore, MRP4 genotyping may be useful for personalizing the therapeutic dose of 6-MP during the ALL maintenance therapy in Japanese.

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Acknowledgements

This study was supported by the Grant-in-Aid for Young Scientists (B) (22790170) and the Grant of National Center for Child Health and Development (25-2).

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Authors and Affiliations

  1. Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University, Tokyo, Japan

    Y Tanaka & T Komiyama

  2. Department of Pediatrics, St Luke’s International Hospital, Tokyo, Japan

    A Manabe

  3. Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan

    H Fukushima, R Suzuki, T Fukushima & R Sumazaki

  4. Department of General Pediatrics and Interdisciplinary Medicine, National Center for Child Health and Development, Tokyo, Japan

    H Nakadate

  5. Department of Pediatrics, St Marianna University School of Medicine, Kanagawa, Japan

    K Kondoh

  6. Department of Pediatrics, Teikyo University Hospital, Tokyo, Japan

    K Nakamura

  7. Department of Hematology/Oncology, Saitama Children’s Medical Center, Saitama, Japan

    K Koh

  8. Department of Hematology/Oncology, Ibaraki Children’s Hospital, Ibaraki, Japan

    M Tsuchida & K Koike

  9. Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan

    N Kiyokawa

  10. Department of Epidemiology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan

    E Noguchi

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  1. Y Tanaka
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  2. A Manabe
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  7. K Nakamura
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  8. K Koh
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  11. K Koike
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Correspondence to Y Tanaka.

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Tanaka, Y., Manabe, A., Fukushima, H. et al. Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia. Pharmacogenomics J 15, 380–384 (2015). https://doi.org/10.1038/tpj.2014.74

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