title: Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia.
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.
authors.affiliation: Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Pediatrics, St Luke's International Hospital, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Manabe
authors.affiliation: Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Fukushima
authors.affiliation: Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Department of General Pediatrics and Interdisciplinary Medicine, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nakadate
authors.affiliation: Department of Pediatrics, St Marianna University School of Medicine, Kanagawa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kondoh
authors.affiliation: Department of Pediatrics, Teikyo University Hospital, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Koh
authors.affiliation: Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Department of Hematology/Oncology, Ibaraki Children's Hospital, Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tsuchida
authors.affiliation: Department of Hematology/Oncology, Ibaraki Children's Hospital, Ibaraki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Koike
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kiyokawa
authors.affiliation: Faculty of Medicine, Department of Epidemiology, University of Tsukuba, Ibaraki, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Noguchi
authors.affiliation: Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Sumazaki
authors.affiliation: Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Komiyama
mesh_terms: D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D011755:Pyrophosphatases / Q000235:genetics; D000097630:Inosine Triphosphatase
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011755:Pyrophosphatases; C073492:ABCC4 protein, human; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase