P322 EXPRESSION OF ORGANIC ANION-TRANSPORTING POLYPEPTIDES (OATP) 1B1 AND 1B3 IN OVARIAN CANCER CELLS: RELEVANCE FOR PACLITAXEL TRANSPORT

Walter Jaeger , Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria
Martin Svoboda , Center for Physiology and Pathophysiology, Medical University of Vienna, Vienna, Austria
Katrin Wlcek , Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria
Barbara Taferner , Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
Steffen Hering , Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
Bruno Stieger , Department of Medicine, University Hospital, Zrich, Switzerland
Theresia Thalhammer , Centre for Physiology and Pathophysiology, Medical University of Vienna, Vienna, Austria

Organic anion transporting polypeptides (OATPs) are known to mediate the uptake of many endogenous compounds and xenobiotics and therefore play a critical role in their absorption, distribution and excretion. Although some of the eleven known human OATP family members have been detected in breast, gastric, liver, pancreatic, and colon carcinomas, the knowledge of their expression in ovarian cancer is still limited. Hence we investigated the transcriptional expression of all 11 OATPs in human malignant ovarian tissue samples (n = 10) and in estrogen-responsive OVCAR-3 and estrogen-independent SK-OV-3 ovarian carcinoma cell lines. Furthermore, by using OATP-transfected Xenopus laevis oocytes we also investigated whether OATPs contribute to cellular paclitaxel uptake. Our data showed that OATP1B1 and OATP1B3 are active paclitaxel transporters (Vmax: 12.3 0.4 fmol/oocyte/min, Km: 0.6 0.04 M. vs. Vmax: 30 1.6 fmol/oocyte/min, Km: 1.6 0.13 M) in transfected X. laevis oocytes. Real-time RT-PCR analysis revealed expression of both OATPs in human ovarian cancer tissue specimens and in cancer cell lines but not in normal ovary tissue. The higher mRNA levels for OATP1B1 and OATP1B3 found in SK-OV-3 as compared with OVCAR-3 cells correlated with a higher initial uptake rate for paclitaxel (Vmax: 1660 126 and 517 86 pmol/mg protein/min). In addition, cytotoxicity studies with OATP1B1- and OATP1B3-transfected SK-OV-3 cells demonstrated lower IC50 values compared to cells transfected with the empty vector. In conclusion, our results revealed OATP1B1 and OATP1B3 as high-affinity paclitaxel transporters expressed in ovarian cancer cell lines and tumor tissues, suggesting a role for these polypeptides in the disposition of paclitaxel during therapy.