title: MS-209, a quinoline-type reversal agent, potentiates antitumor efficacy of docetaxel in multidrug-resistant solid tumor xenograft models.
abstract: The existence of multidrug-resistant (MDR) cells in cancer is a major obstacle to effective cancer chemotherapy. Expression of P-glycoprotein (P-gp) in cancer cells causes resistance against paclitaxel and docetaxel, as well as against vincristine and doxorubicin (ADM). MS-209 is a novel MDR-reversal agent currently under clinical evaluation, which is shown to be active against ADM and vincristine resistance in MDR cancer cells in vitro and in vivo. In this paper, we report the combined effect of MS-209 with docetaxel in various MDR cancer cell lines that express P-gp. MS-209 at 3 microM effectively overcame docetaxel resistance in MDR cancer cells, and this concentration was achieved in blood plasma for > 7 h without serious toxicity. To study the effect of MS-209 in a clinically relevant model, we compared the antitumor efficacy of docetaxel alone with that of docetaxel combined with MS-209 at equitoxic doses in established solid tumor xenograft models. Treatment with docetaxel alone at the maximal tolerated dose (MTD) showed an apparent antitumor activity to an intrinsically resistant HCT-15 tumor xenograft, and MS-209 additionally potentiated the antitumor activity of docetaxel. Against a MCF-7/ADM tumor xenograft expressing larger amounts of P-gp, docetaxel alone at the MTD showed no antitumor activity, whereas the MTD of docetaxel combined with MS-209 greatly reduced MCF-7/ADM tumor growth. These results indicate that MS-209 could be a clinically useful drug to modulate MDR in docetaxel therapy.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032.
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Naito
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsuba
authors.forename: Shigeo
authors.initials: S
authors.lastname: Sato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirata
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsuruo
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008938:Mitosis; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011804:Quinolines; D043823:Taxoids; C087719:dofequidar; D000077143:Docetaxel; D017239:Paclitaxel