Article

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

University Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.39). 03/2008; 83(2):258-64. DOI: 10.1038/sj.clpt.6100268
Source: PubMed

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.

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    • "Decreasing hOCT1 levels cause a low intracellular concentration of imatinib in the cytoplasm, and therefore the therapeutic activity of the drug is weakened in the cell (Wang et al., 2008). As a second-line treatment agent, nilotinib is administered to imatinib-resistant patients with CML. "
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    • "The most established cause of secondary resistance is the occurrence of mutations in the catalytic domain of the kinase, which restrict the binding of currently available TKIs (Levitzki and Mishani, 2006). In addition, primary or secondary resistance may result from insufficient intracellular drug concentrations , due to poor uptake (Wang et al., 2008; Engler et al., 2011; Mandery et al., 2012) or active efflux transport (Ozvegy- Laczka et al., 2005; Eadie et al., 2014). Two prominent transporters involved in drug efflux from cells are P-gp (multidrug resistance Abbreviations: ABC, adenosine triphosphate binding cassette; BCRP, breast cancer resistance protein; EGFR, epidermal growth factor receptor; EGFRI, epidermal growth factor receptor kinase inhibitor; FTC, fumitremorgin C; PET, positron emission tomography; P-gp, P-glycoprotein; TKI, tyrosine kinase inhibitor. "
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    • "Membrane transporters are major determinants of drug pharmacokinetics and pharmacodynamics. The human organic cation transporter 1 (hOCT-1, SLC22A1), an influx transporter, is responsible for the uptake of imatinib into CML cells [17] [18] [19]. One of the causes of inter-patient differences in imatinib uptake may be variable function of hOCT-1. "
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