title: Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia.
abstract: Some chronic myeloid leukemia (CML) patients do not respond to imatinib, whereas others lose an initial response. To identify potential imatinib failures, we investigated the expression of imatinib uptake transporter (human organic cation transporter 1; hOCT1) and efflux transporters (ATP-binding cassette transporters ABCB1, ABCG2, and ABCC1) using real-time quantitative reverse transcription-polymerase chain reaction in 70 CML patients. Patients with high pretreatment hOCT1 expression had superior complete cytogenetic response (CCR) rates (P=0.008), progression-free and overall survival (P=0.01 and 0.004). Pretreatment ABCB1, ABCG2, and ABCC1 levels did not correlate with treatment outcome. Regression analysis demonstrated that pretreatment hOCT1 expression was the most powerful predictor of CCR achievement at 6 months (P=0.002). Imatinib uptake into a CML cell line with high hOCT1 expression was greater than into those with modest or low expression (P=0.002). The expression of hOCT1, but not efflux transporters, is important in determining the clinical response to imatinib.
authors.affiliation: University Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Giannoudis
authors.forename: S
authors.initials: S
authors.lastname: Lane
authors.forename: P
authors.initials: P
authors.lastname: Williamson
authors.forename: M
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: R E
authors.initials: RE
authors.lastname: Clark
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D001549:Benzamides; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D016044:Fusion Proteins, bcr-abl; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D050811:Octamer Transcription Factor-1 / Q000235:genetics / Q000378:metabolism*; D018579:Patient Selection; D010879:Piperazines / Q000378:metabolism / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism / Q000627:therapeutic use*; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; C419353:ABCG1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001549:Benzamides; D009363:Neoplasm Proteins; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl