REVERSAL OF MULTIDRUG-RESISTANCE BY A NOVEL QUINOLINE DERIVATIVE, MS-209

MS-209, a novel quinoline derivative, was examined for its reversing e ffect on multidrug-resistant tumor cells. MS-209 at 1-10 mu M complete ly reversed resistance against vincristine (VCR) in vitro in multidrug -resistant variants of mouse leukemia P388 cells (VCR-resistant P388/V CR and Adriamycin (ADM)-resistant P388/ADM) and human leukemia K562 ce lls (VCR-resistant K562/VCR and ADM-resistant K562/ADM). MS-209 at 1-1 0 mu M also completely reversed resistance against ADM in vitro in P38 8/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 chemotherape utic 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 mu g/kg VCR, a treated/control (T/C) value of 155% was obtained. MS-209 a lso enhanced the chemotherapeutic effect of ADM in P388/ADM-bearing mi ce. The most prominent effects were obtained when MS-209 was given wit h 2 mg/kg ADM, yielding T/C values of 150%-194% for the combined treat ment at an MS-209 dose of 200-450 mg/kg. MS-209 inhibited [H-3]-azidop ine photolabeling of P-glycoprotein efficiently Furthermore, the accum ulation of ADM in K562/ADM cells was increased more efficiently by MS- 209 than by verapamil. These results indicate that MS-209, like verapa mil, directly interacts with P-glycoprotein and inhibits the active ef flux of antitumor agents, thus overcoming multidrug resistance in vitr o and in vivo.