Reversal of multidrug resistance by a novel quinoline derivative,MS-209 |
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Authors: | Wakao Sato Nobuyuki Fukazawa Osamu Nakanishi Makoto Baba Tsuneji Suzuki Osamu Yano Mikihiko Naito Takashi Tsuruo |
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Affiliation: | (1) Institute of Biological Science, Mitsui Pharmaceuticals, Inc., 297 Mobara-shi, Chiba, Japan;(2) Life Science Laboratory, Mitsui Toatsu Chemicals, Inc., 297 Mobara-shi Chiba, Japan;(3) Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, 113 Tokyo, Japan;(4) Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Kami-ikebukuro, Toshima-ku, 170 Tokyo, Japan |
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Abstract: | MS-209, a novel quinoline derivative, was examined for its reversing effect on multidrug-resistant tumor cells. MS-209 at 1–10 M completely reversed resistance against vincristine (VCR) in vitro in multidrug-resistant variants of mouse leukemia P388 cells (VCR-resistant P388/VCR and Adriamycin (ADM)-resistant P388/ADM) and human leukemia K562 cells (VCR-resistant K562/VCR and ADM-resistant K562/ADM). MS-209 at 1–10 M also completely reversed resistance against ADM in vitro in P388/VCR cells, K562/VCR cells, and K562/ADM cells. In ADM-resistant P388 (P388/ADM) cells, however, ADM resistance was only partially reversed at the MS-209 concentrations tested. MS-209 enhanced the chemotherapeutic effect of VCR in P388/VCR-bearing mice. When MS-209 was given p.o. at 80 mg/kg twice a day (total dose, 160 mg/kg per day) with 100 g/kg VCR, a treated/control (T/C) value of 155% was obtained. MS-209 also enhanced the chemotherapeutic effect of ADM in P388/ADM-bearing mice. The most prominent effects were obtained when MS-209 was given with 2 mg/kg ADM, yielding T/C values of 150%–194% for the combined treatment at an MS-209 dose of 200–450 mg/kg. MS-209 inhibited [3H]-azidopine photolabeling of P-glycoprotein efficiently. Furthermore, the accumulation of ADM in K562/ADM cells was increased more eficiently by MS-209 than by verapamil. These results indicate that MS-209, like verapamil, directly interacts with P-glycoprotein and inhibits the active efflux of antitumor agents, thus overcoming multidrug resistance in vitro and in vivo.This work was supported by grants-in-aid from the Ministry of Education Science and Culture, Japan |
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Keywords: | MS-209 Quinoline Multidrug resistance |
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