Effect of MDR antagonists on the cidal activity of vincristine for cells expressing MDR-1 is superior to those expressing MRP.
In an attempt to identify the target protein, P-GP or mrp, of each MDR antagonist, verapamyl (Ver), dipyridamole (Dip), or cyclosporin A (Cy-A), this study was designed to compare the activity of the three afore-mentioned drugs and to test their combined effect on the cidal activity of vincristine (VCR) in five types of wild and the corresponding VCR-resistant cultured cell lines from human leukemia and lymphoma. Three of the VCR-resistant cell lines are characterized by the overexpression of mdr-1, while two cell lines overexpress mrp. We found that all three antagonists additively to synergistically enhanced the cidal activity of VCR for the five wild-type and VCR-resistant cell lines in a dose dependent manner when used singly. Combinations consisting of a 20% inhibitory concentration (IC20) of VCR plus two antagonists also showed additive to synergistic effects on both wild and VCR-resistant cell lines. It is of interest that the combined effect of IC20 VCR plus MDR antagonists on the three VCR-resistant cell lines expressing mdr-1 was significantly superior to those of the two cell lines expressing the mrp gene. These results suggest that the combined effect of MDR antagonists work better than their single use and that the MDR antagonists work more efficiently in cells showing drug resistance through mdr-1 than in those utilizing mrp.
School of Medical Science, The University of Tokushima, Tokushima City, Tokushima 770, Japan.
E
E
Hosoi
M
M
Hirose
S
S
Hamano
M
M
Morimoto
Y
Y
Kuroda
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D004176:Dipyridamole / Q000494:pharmacology*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D016572:Cyclosporine; D004176:Dipyridamole; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D014700:Verapamil; D014750:Vincristine