title: Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia.
abstract: The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P=0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P=0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P=0.01/P<0.0001). We observed more liver toxicity after high-dose methotrexate in patients with 3435CC variant versus 3435CT/TT (P=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G>A may be a new possible predictive marker for outcome in childhood ALL.
authors.affiliation: 1] Clinical Pharmacology, Faculty of Health Sciences, Division of Drug Research, Department of Medical and Health Sciences, Linköpings Universitet, Linköping, Sweden [2] Laboratory of Molecular Medicine, Department of Clinical Immunology 7631, Rigshospitalet, University Hospital in Copenhagen, Copenhagen, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Gregers
authors.affiliation: 1] Clinical Pharmacology, Faculty of Health Sciences, Division of Drug Research, Department of Medical and Health Sciences, Linköpings Universitet, Linköping, Sweden [2] Science for Life Laboratory, Division of Gene Technology, School of Biotechnology, KTH Royal Institute of Technology, Solna, Sweden [3] Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Gréen
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.
authors.forename: I J
authors.initials: IJ
authors.lastname: Christensen
authors.affiliation: Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Dalhoff
authors.affiliation: Department of Pediatric, University Hospital in Skejby, Aarhus, Denmark.
authors.forename: H
authors.initials: H
authors.lastname: Schroeder
authors.affiliation: Department of Pediatric, University Hospital in Odense, Odense, Denmark.
authors.forename: N
authors.initials: N
authors.lastname: Carlsen
authors.affiliation: Department of Pediatric, University Hospital in Aalborg, Aalborg, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Rosthoej
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Lausen
authors.affiliation: 1] Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark [2] The Medical Faculty, Institute of Gynecology, Obstetrics and Pediatrics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Schmiegelow
authors.affiliation: Clinical Pharmacology, Faculty of Health Sciences, Division of Drug Research, Department of Medical and Health Sciences, Linköpings Universitet, Linköping, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Peterson
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000208:Acute Disease; D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003718:Denmark / Q000453:epidemiology; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use; D011110:Polymorphism, Genetic / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*; D011237:Predictive Value of Tests; D012008:Recurrence; D018570:Risk Assessment; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D008727:Methotrexate