Protection by inhibitors of multidrug resistance against mitochondrial mutagenesis in Saccharomyces cerevisiae.
A number of inhibitors thought to act on the drug efflux mechanism of multidrug-resistant cells have been tested for their ability to inhibit the induction of respiration-deficient (petite) colonies of the yeast Saccharomyces cerevisiae by mitochondrial mutagens. The mutagens tested were 3,6-diamino-9-(4-[(methylsulphonyl)aminophenyl]amino) acridine (an antitumour compound related to both amsacrine and proflavine), ethidium bromide, quinolinium dibromide (NSC 176319, a non-intercalative DNA binding antileukaemia agent) and rhodamine 123. The inhibitors tested included verapamil, perhexiline, chlorpromazine, trifluoperazine, reserpine, chloroquine, quinacrine, tamoxifen, clomiphene, cyclosporin A, valinomycin, amphotericin B and Tween 80. Several of these agents protected against mitochondrial mutagenesis, the most active being verapamil, reserpine, chloroquine, cyclosporin A and Tween 80. The correspondence between activity against multidrug resistance and activity in the yeast system strongly implies some degree of similarity in mechanisms for drug efflux from multidrug-resistant cells and drug uptake into the mitochondria of yeast. Agents protecting against the uptake of drugs into mitochondria of mammalian cells may have use in minimizing the long-term toxicity of anticancer drugs mediated by mitochondrial drug retention.
Baguley
B C
BC
Cancer Research Laboratory, University of Auckland Medical School, New Zealand.
Turner
P M
PM
Ferguson
L R
LR
D000609:Aminoacridines / Q000037:antagonists & inhibitors; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance; D008928:Mitochondria / Q000187:drug effects*; D009153:Mutagens; D009154:Mutation; D011136:Polysorbates / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects*; D014700:Verapamil / Q000494:pharmacology
D000609:Aminoacridines; D009153:Mutagens; D011136:Polysorbates; C063556:3,6-diamino-9-(4-(methylsulfonyl)aminophenyl)aminoacridine; D002738:Chloroquine; D014700:Verapamil