INCREASED SENSITIVITY TO VINCRISTINE OF MDR CELLS BY THE LEUKOTRIENE D-4 RECEPTOR ANTAGONIST, ONO-1078

The leukotriene D-4 (LTD4) receptor antagonist, xy)benzoylamino]-2-(te trazol-5-yl)-4H-1-benzopyran hemihydrate (ONO-1078) is used for the tr eatment of allergic asthma and other immediate hypersensitivity diseas es. We examined the effect of ONO-1078 on the sensitivity to vincristi ne (VCR) of MRP overexpressing multidrug-resistant CV60 and its parent al 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-107 8 at the maximum non-toxic concentration (100 mu M). The VCR sensitivi ty of multidrug-resistant KB-C2 cells that overexpressed P-gp was incr eased 2.6-fold by ONO-1078. The accumulation of VCR in KB-3-1, CV60 an d KB-C2 cells was significantly increased by ONO-1078. The efflux of V CR from KB-3-1 cells was not inhibited, but that from CV60 cells was e nhanced compared with that from KB-3-1 cells and was partially inhibit ed by ONO-1078. ONO-1078 competitively inhibited the ATP-dependent [H- 3]LTC4 uptake in membrane vesicles isolated from CV60 cells. These fin dings 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. (C) 1998 Elsevier Science Irel and Ltd. All rights reserved.