Expression of the Uptake Drug Transporter hOCT1 is an Important Clinical Determinant of the Response to Imatinib in Chronic Myeloid Leukemia

• Published in: Clinical pharmacology and therapeutics 2008-02, Vol.83 (2), p.258-264
• Main Authors: Wang, L, Giannoudis, A, Lane, S, Williamson, P, Pirmohamed, M, Clark, RE
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - metabolism; Antineoplastic Agents - therapeutic use; ATP Binding Cassette Transporter, Sub-Family B; ATP Binding Cassette Transporter, Sub-Family G, Member 1; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Benzamides; Biological and medical sciences; Cell Line, Tumor; Disease-Free Survival; Fusion Proteins, bcr-abl; Gene Expression Regulation, Neoplastic; Hematologic and hematopoietic diseases; Humans; Imatinib Mesylate; Leukemia, Myeloid - drug therapy; Leukemia, Myeloid - genetics; Leukemia, Myeloid - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Middle Aged; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Octamer Transcription Factor-1 - genetics; Octamer Transcription Factor-1 - metabolism; Patient Selection; Pharmacology. Drug treatments; Piperazines - metabolism; Piperazines - therapeutic use; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Pyrimidines - metabolism; Pyrimidines - therapeutic use; Regression Analysis; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Transfection; Treatment Outcome
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1038/sj.clpt.6100268

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. Clinical Pharmacology & Therapeutics (2008) doi:10.1038/sj.clpt.6100268