Localization of a nonintercalative DNA binding antitumour drug in mitochondria: relationship to multidrug resistance.
The bis-(n-butyl) quaternary salt of N,N'-bis-(6-quinolyl)terephthalamide (QBQ), a fluorescent antitumour compound in the phthalanilide series which is thought to bind to the minor groove of the DNA double helix, has been investigated with respect to its in vitro activity and subcellular localization. Cultured MCF-7 human breast carcinoma cells concentrated QBQ in mitochondria by a time-dependent process which was inhibited by the ionophore valinomycin, suggesting a possible mode of antitumour action of QBQ through mitochondrial poisoning. Growth of cultured P388 murine leukaemia cells was inhibited 50% in the presence of 0.52 microM QBQ and multidrug-resistant P388 sublines developed for resistance to actinomycin D, vincristine, Adriamycin and the phthalanilide NSC 38280 were cross-resistant to the drug. Cross-resistance was reduced in all lines by the presence of 11 microM verapamil, suggesting that a transport resistance mechanism operates on QBQ. The actinomycin D-resistant P388 cell line was found to be cross-resistant to the aromatic cations rhodamine 123, which binds to proteins, and ethidium and pyronin Y, which bind intercalatively to DNA. Thus mitochondrion-specific drugs with different macromolecular binding properties all appear to be excluded by multidrug-resistant cells.
Liley
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DT
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Wiggins
P M
PM
Baguley
B C
BC
D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis*; D001943:Breast Neoplasms / Q000032:analysis*; D004351:Drug Resistance; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D008928:Mitochondria / Q000032:analysis*; D010797:Phthalimides; D011804:Quinolines; D014407:Tumor Cells, Cultured / Q000032:analysis
D000970:Antineoplastic Agents; D010797:Phthalimides; D011804:Quinolines; C061649:bis-(n-butyl)-N,N'-bis-(6-quinoyl)terephthalamide