title: Modulation of OATP1B-type transporter function alters cellular uptake and disposition of platinum chemotherapeutics.
abstract: Expression of the human organic anion transporting polypeptides OATP1B1 and OATP1B3 has been previously believed to be restricted to hepatocytes. Here we show that the gene encoding OATP1B3, but not OATP1B1, is abundantly expressed in multiple human solid tumors that include hepatocellular, lung, and ovarian carcinomas. Surprisingly, OATP1B3 gene expression in a panel of 60 human tumor cell lines was linked with sensitivity to multiple cytotoxic agents, including the platinum anticancer drugs cisplatin, carboplatin, and oxaliplatin. In addition, overexpression of OATP1B3 in mammalian cells increased cellular accumulation of platinum agents and decreased cell survival. In mice with a targeted disruption of the ortholog transporter Oatp1b2, the liver-to-plasma ratio of cisplatin was significantly reduced compared with wild-type mice, without concurrent changes in expression profiles of other transporter genes. Our findings indicate an unexpected role for tumoral and host OATP1B-type carriers in the toxicity and disposition of platinum anticancer drugs, and may provide a foundation for understanding the extensive interindividual pharmacodynamic variability seen with these drugs in patients.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Lancaster
authors.forename: Jason A
authors.initials: JA
authors.lastname: Sprowl
authors.forename: Aisha L
authors.initials: AL
authors.lastname: Walker
authors.forename: Shuiying
authors.initials: S
authors.lastname: Hu
authors.forename: Alice A
authors.initials: AA
authors.lastname: Gibson
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001692:Biological Transport; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D010984:Platinum / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D000970:Antineoplastic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D010984:Platinum