title: Differential expression of drug uptake and efflux transporters in Japanese patients with hepatocellular carcinoma.
abstract: Targeted chemotherapy for hepatocellular carcinoma (HCC) is impaired by intrinsic and/or acquired drug resistance. Because drugs used in HCC therapy (e.g., anthracyclines or the tyrosine kinase inhibitor sorafenib) are substrates of uptake and/or efflux transporters, variable expression of these transporters at the plasma membrane of tumor cells may contribute to drug resistance and subsequent clinical response. In this study, the variability of expression of uptake transporters [organic cation transporter (OCT) 1 and OCT3] and efflux transporters [multidrug resistance 1 (MDR1)/P-glycoprotein, multidrug resistance protein (MRP) 1, MRP2, and breast cancer resistance protein (BCRP)], selected for their implication in transporting drugs used in HCC therapy, was investigated. HCC and corresponding nontumor tissue samples were collected from 24 Japanese patients at the time of surgery. Protein expression was determined by immunohistochemistry. Expression data were correlated with clinicopathological characteristics and patients' outcome (median follow-up, 53 months). Generally, expression was highly variable among individual tumor samples. Yet median expression of OCT1, OCT3, and MDR1 in HCC was significantly lower (1.4-, 2.7-, and 2-fold, respectively) than in nontumor tissue, while expression of MRP2 persisted and BCRP showed a trend of increased levels in HCC. Patients with low BCRP expression had significantly shorter overall and recurrence-free survival times. Results suggest different expression patterns of drug transporters in HCC, which are associated only in part with clinicopathological characteristics. Detailed information on expression of drug transporters in HCC may be promising for individualization and optimization of drug therapy for liver cancer.
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (T.N., E.S., P.F., M.S., A.T.N.); Third Department of Internal Medicine (T.N., H.F., H.Y.) and Department of Surgery (Y.N.), Nara Medical University, Kashihara, Japan; and Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany (M.S.).
authors.forename: Tadashi
authors.initials: T
authors.lastname: Namisaki
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (T.N., E.S., P.F., M.S., A.T.N.); Third Department of Internal Medicine (T.N., H.F., H.Y.) and Department of Surgery (Y.N.), Nara Medical University, Kashihara, Japan; and Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany (M.S.).
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (T.N., E.S., P.F., M.S., A.T.N.); Third Department of Internal Medicine (T.N., H.F., H.Y.) and Department of Surgery (Y.N.), Nara Medical University, Kashihara, Japan; and Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany (M.S.).
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukui
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (T.N., E.S., P.F., M.S., A.T.N.); Third Department of Internal Medicine (T.N., H.F., H.Y.) and Department of Surgery (Y.N.), Nara Medical University, Kashihara, Japan; and Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany (M.S.).
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (T.N., E.S., P.F., M.S., A.T.N.); Third Department of Internal Medicine (T.N., H.F., H.Y.) and Department of Surgery (Y.N.), Nara Medical University, Kashihara, Japan; and Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany (M.S.).
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nakajima
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (T.N., E.S., P.F., M.S., A.T.N.); Third Department of Internal Medicine (T.N., H.F., H.Y.) and Department of Surgery (Y.N.), Nara Medical University, Kashihara, Japan; and Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany (M.S.).
authors.forename: Peter
authors.initials: P
authors.lastname: Fritz
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (T.N., E.S., P.F., M.S., A.T.N.); Third Department of Internal Medicine (T.N., H.F., H.Y.) and Department of Surgery (Y.N.), Nara Medical University, Kashihara, Japan; and Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany (M.S.).
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (T.N., E.S., P.F., M.S., A.T.N.); Third Department of Internal Medicine (T.N., H.F., H.Y.) and Department of Surgery (Y.N.), Nara Medical University, Kashihara, Japan; and Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany (M.S.) anne.nies@ikp-stuttgart.de.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Nies
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D044466:Asian People / Q000235:genetics*; D001692:Biological Transport / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D027702:Organic Cation Transporter 1 / Q000235:genetics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D050814:Octamer Transcription Factor-3; D027702:Organic Cation Transporter 1; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C494173:POU5F1 protein, human