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: 7.9). 03/2008; 83(2):258-64. DOI: 10.1038/sj.clpt.6100268
Source: PubMed


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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    ABSTRACT: Chronic myeloid leukemia (CML) is characterized by the accumulation of Philadelphia chromosome-positive (Ph+) myeloid cells. Ph+ cells occur via a reciprocal translocation between the long arms of chromosomes 9 and 22 resulting in constitutively active Bcr-abl fusion protein. Tyrosine kinase inhibitors (TKIs) are used against the kinase activity of Bcr-abl fusion protein for the effective treatment of CML. However, the development of drug resistance, directed by different genetic mechanisms, is the major problem of clinical applications of TKIs. These mechanisms include mutations in the TKI binding site of Bcr-abl, overexpression of Bcr-abl, overexpression of ATP binding cassette transporters, aberrant ceramide metabolism, inhibition of apoptosis, and changes in expression levels of microRNAs. Recently, many studies have focused on understanding the molecular mechanisms of drug resistance in cancer while targeting therapies providing reversal of resistance. Cancer stem cells also have roles in tumor initiation, maintenance, progression, metastasis, and drug resistance. Uncovering the mechanisms of drug resistance can provide more efficient treatment of cancer since these findings may provide novel targets for a complete cure. In this review, we discuss recent findings on the mechanisms of multidrug resistance and its reversal in 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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    ABSTRACT: The objective of this study was to investigate in vitro the interactions between novel epidermal growth factor receptor kinase inhibitors (EGFRIs) developed for positron emission tomography (PET) imaging and the major efflux transporter breast cancer resistance protein (BCRP/ABCG2). Seven compounds were evaluated, using the ATPase activity assays and Madin-Darbey canine kidney (MDCK) cells overexpressing BCRP. Five of the tested compounds activated BCRP ATPase to various extent. Overexpression of BCRP conferred resistance to ML04, ML06, methoxy-Br-ML03, and PEG6-ML05 (IC50 values for inhibition of control cell proliferation 2.1 ± 0.6, 2.2 ± 0.7, 1.8 ± 1.2, and 2.8 ± 3.1 μM, respectively, compared to >50 μM in MDCK-BCRP cells). At submicromolar concentrations, none of the EGFRIs significantly inhibited BCRP. Immunoblotting studies indicated that BCRP expression is evident in cell lines utilized for in vivo tumor grafting in small animal PET imaging studies. Thus, the intensity of EGFRIs radioactivity signals previously observed in tumor xenografts reflects an interplay between transporter-mediated distribution of the probe into tumor cells and target binding. Concomitant use of efflux transporter inhibitors may help distinguish between the contribution of efflux transport and EGFR binding to the tissue signal.
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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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    ABSTRACT: The therapeutic approach in chronic myeloid leukemia (CML) has undergone a revolutionary change during the last 2 decades with the introduction of the tyrosine kinase inhibitors. The use of these agents has changed overall survival as well as the quality of life of CML patients. Since the introduction of imatinib, newer agents have been developed and their role as first line treatment was examined. The use of genomics and proteomics as a means to tailor treatment of CML patients is underway. Meanwhile, clinical parameters as disease phase and response to treatment are used to guide a personalized approach. In this review, we will discuss the various aspects of personalized medicine in CML, including the use of the different scoring systems to guide treatment, disease phase as a means to choose the proper approach and the value of early response evaluation in decision-making. The approach towards patients resistant to tyrosine kinase inhibitors, individual strategies for discontinuation of TKIs and "operational" cure in CML will also be discussed and finally the personalized treatment for CML patients in the near future based on present outcomes.
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