Reversal of multidrug resistance by two novel indole derivatives.
Two new fused indoles were found to overcome multidrug resistance in P388/Adr cells in vitro. These agents potentiated the cytotoxicity of the antitumor drugs Adriamycin, vinblastine, and vincristine in multidrug-resistant cells with no effect on drug-sensitive parent P388 cells. They significantly increased the ATP-dependent accumulation of [3H]-vinblastine and inhibited efflux of the labeled drug from resistant cells. These compounds also inhibited photoaffinity labeling of P-glycoprotein by [3H]azidopine in P388/Adr cells and membranes isolated from these cells. In addition, the calcium antagonist activity of these compounds was very weak compared with that of verapamil. These data suggest that the compounds reported here may specifically overcome multidrug resistance without the serious hypotensive effects associated with calcium antagonists and that this activity may be independent of their ability to block calcium transport.
Abbott Laboratories, Abbott Park, Illinois 60064.
S
S
Kadam
M
M
Maus
J
J
Poddig
S
S
Schmidt
R
R
Rasmussen
E
E
Novosad
J
J
Plattner
J
J
McAlpine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects; D004351:Drug Resistance; D004357:Drug Synergism; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051381:Rats; D014407:Tumor Cells, Cultured; D014661:Vasoconstriction / Q000187:drug effects; D014700:Verapamil / Q000633:toxicity; D014747:Vinblastine / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D015220:Calcium Channels; D007211:Indoles; D008562:Membrane Glycoproteins; C076353:A 30312; C076352:A 39355; D014747:Vinblastine; D014700:Verapamil; D002118:Calcium