Increased sensitivity to vincristine of MDR cells by the leukotriene D4 receptor antagonist, ONO-1078.
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 microM). 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.
Nagayama
S
S
The Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Sakuragaoka, Japan.
Chen
Z S
ZS
Kitazono
M
M
Takebayashi
Y
Y
Niwa
K
K
Yamada
K
K
Tani
A
A
Haraguchi
M
M
Sumizawa
T
T
Furukawa
T
T
Aikou
T
T
Akiyama
S
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020024:Leukotriene Antagonists; D017998:Leukotriene D4 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D002867:Chromones; D020024:Leukotriene Antagonists; D009363:Neoplasm Proteins; D014750:Vincristine; D017998:Leukotriene D4; C047681:pranlukast