Author/Authors :
Nagayama، نويسنده , , Shuichi and Chen، نويسنده , , Zhe-Sheng and Kitazono، نويسنده , , Masaki and Takebayashi، نويسنده , , Yuji and Niwa، نويسنده , , Kiyoshi and Yamada، نويسنده , , Kazutaka and Tani، نويسنده , , Ayako and Haraguchi، نويسنده , , Misako and Sumizawa، نويسنده , , Tomoyuki and Furukawa، نويسنده , , Tatsuhiko and Aikou، نويسنده , , Takashi and Akiyama، نويسنده , , Shin-ichi، نويسنده ,
Abstract :
The leukotriene D4 (LTD4) receptor antagonist, 4-oxo-8-[p-(4-phenylbutyloxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate (ONO-1078) is used for the treatment of allergic asthma and other immediate hypersensitivity diseases. We examined the effect of ONO-1078 on the sensitivity to vincristine (VCR) of MRP overexpressing multidrug-resistant CV60 and its parental drug-sensitive KB-3-1 cell lines. The sensitivity to VCR of KB-3-1 and CV60 cells was increased 13- and 15-fold, respectively, by ONO-1078 at the maximum non-toxic concentration (100 μM). The VCR sensitivity of multidrug-resistant KB-C2 cells that overexpressed P-gp was increased 2.6-fold by ONO-1078. The accumulation of VCR in KB-3-1, CV60 and KB-C2 cells was significantly increased by ONO-1078. The efflux of VCR from KB-3-1 cells was not inhibited, but that from CV60 cells was enhanced compared with that from KB-3-1 cells and was partially inhibited by ONO-1078. ONO-1078 competitively inhibited the ATP-dependent [3H]LTC4 uptake in membrane vesicles isolated from CV60 cells. These findings suggest that ONO-1078 inhibits the transporting activity of MRP and that ONO-1078 increases the sensitivity to VCR of KB-3-1 cells by increasing the VCR uptake in the cells.
