title: Polymorphisms in the human organic cation transporter and the multidrug resistance gene: correlation with imatinib levels and clinical course in patients with chronic myeloid leukemia.
abstract: The optimal tyrosine kinase inhibitor for any individual patient with chronic myeloid leukemia (CML) is not predictable. Pharmacogenetic parameters and trough levels of imatinib (IM) have each been independently correlated with response. We therefore studied the human organic cation transporter (hOCT1) and multidrug resistance (MDR1) single nucleotide polymorphisms (SNPs) and correlated these with IM levels and major molecular response (MMR) (3-log reduction) in 84 patients with CML, the first such study performed in Caucasians. We studied MDR1 G2677T and C3435T, and for hOCT1, C480G and A1222G. IM levels varied significantly with dose (< or > 400 mg/day) (p = 0.038) and were significantly lower in 20 patients who lost MMR (p = 0.042). Adjusting for dose, trough IM levels were not significantly correlated with SNPs. Patients with MDR1 3435 TT had significantly longer times to MMR compared to CC/CT genotypes (p = 0.047). Genotypes did not predict treatment failure when controlling for IM levels. We conclude that IM levels, but not the SNPs studied here, determine IM failure.
authors: Department of Medicine, Hebrew University-Hadassah Medical School , Jerusalem , Israel.
authors: Jacob
authors: J
authors: Vine
authors: Sara Bar
authors: SB
authors: Cohen
authors: Rosa
authors: R
authors: Ruchlemer
authors: Neta
authors: N
authors: Goldschmidt
authors: Moshe
authors: M
authors: Levin
authors: Diana
authors: D
authors: Libster
authors: Alexander
authors: A
authors: Gural
authors: Moshe E
authors: ME
authors: Gatt
authors: David
authors: D
authors: Lavie
authors: Dina
authors: D
authors: Ben-Yehuda
authors: Deborah
authors: D
authors: Rund
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000097:blood / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D053208:Kaplan-Meier Estimate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D027702:Organic Cation Transporter 1 / Q000235:genetics*; D010879:Piperazines / Q000097:blood / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000627:therapeutic use; D011743:Pyrimidines / Q000097:blood / Q000627:therapeutic use*; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001549:Benzamides; D027702:Organic Cation Transporter 1; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: ABCB1; SLC22A1; Tyrosine kinase inhibitors; pharmacogenetics; prognosis