1. Academic Validation
  2. MS-209, a quinoline-type reversal agent, potentiates antitumor efficacy of docetaxel in multidrug-resistant solid tumor xenograft models

MS-209, a quinoline-type reversal agent, potentiates antitumor efficacy of docetaxel in multidrug-resistant solid tumor xenograft models

  • Clin Cancer Res. 2002 Feb;8(2):582-8.
Mikihiko Naito 1 Yasuhiro Matsuba Shigeo Sato Hiroshi Hirata Takashi Tsuruo
Affiliations

Affiliation

  • 1 Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032.
PMID: 11839680
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.

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