CHLORAMBUCIL-TAUROCHOLATE IS TRANSPORTED BY BILE-ACID CARRIERS EXPRESSED IN HUMAN HEPATOCELLULAR CARCINOMAS

Background & Aims: Chemotherapy of hepatocellular carcinomas is hamper ed by the insufficient accumulation of cytostatic drugs within the tum or cells. The aim of this study was to evaluate the feasibility of the rapeutic strategies using antineoplastic agents coupled to bile acids. Methods: Expression of the Na+-taurocholate-cotransporting polypeptid e (NTCP) was analyzed in six hepatocellular carcinomas and in nonmalig nant liver tissue. Uptake of the cytostatic drug [H-3]chlorambucil-tau rocholate (S2676) was measured in Xenopus laevis oocytes injected with total messenger RNA (mRNA) from the carcinomas or peritumor tissue or with complementary RNA encoding the NTCP or the organic anion-transpo rting polypeptide (OATP) of human liver. Results: Expression of hepato cellular carcinoma mRNA in oocytes resulted in mainly Na+-dependent up take of chlorambucil-taurocholate. The level of NTCP mRNA in carcinoma s amounted to 56% +/- 27% compared with peritumor tissue. Immunofluore scence studies confirmed the expression of NTCP on the surface of hepa tocellular carcinoma cells. OATP expression, determined by immunoblott ing, was similar in hepatocellular carcinomas and surrounding liver ti ssue (n = 3). NTCP mediated Na+-dependent uptake of chlorambucil-tauro cholate (Michaelis constant, 11 mu mol/L), whereas OATP mediated Na+-i ndependent uptake. Conclusions: Hepatocellular carcinomas express the Na+- dependent bile acid transporter NTCP. Because NTCP mediates high- affinity uptake of chlorambucil-taurocholate, targeting of cytostatic bile acids to hepatocellular carcinomas could become a feasible therap eutic strategy.