Reversal of multidrug resistance by a new lipophilic cationic molecule, S9788. Comparison with 11 other MDR-modulating agents in a model of doxorubicin-resistant rat glioblastoma cells.
We have compared the properties of the novel multidrug resistance modulator, S9788, to a panel of 11 well-known modulators in a model of rat glioblastoma cells resistant to doxorubicin and displaying a P-glycoprotein-mediated multidrug-resistance phenotype complemented by a mechanism of intracellular drug tolerance not yet identified (Br J Cancer 1992, 65, 538-544). S9788, like most modulators, was able to completely restore drug accumulation in the resistant line to the level obtained in the sensitive cells. This was obtained with 10 mumol/l of modulator, which is slightly higher than required for cyclosporine A (3 mumol/l) verapamil and nicardipine (6 mumol/l), but lower than for amiodarone, trifluoperazine and dipyridamole (20 mumol/l), tamoxifen and diltiazem (40 mumol/l), quinine, quinidine and nifedipine (> 100 mumol/l). Complete restoration of drug cytotoxicity was, however, obtained only with amiodarone, and a residual resistance factor of 4 could not be overcome by cyclosporine A or S9788, while other modulators gave residual resistance factors of 5-20 (trifluoperazine, tamoxifen, verapamil, quinine, nicardipine, dipyridamole) or even higher (diltiazem, quinidine, nifedipine). When studying doxorubicin accumulation obtained for an exposure to the IC50 of this drug, it appeared that some modulators were able to decrease this "intracellular IC50" independently of their efficiency in resistance reversal (cyclosporine A, S9788, amiodarone, trifluoperazine, quinine, tamoxifen), thus reversing intracellular drug tolerance, whereas other modulators could not reduce this parameter (verapamil, nicardipine, dipyridamole, diltiazem, quinidine). It is suggested that drugs of the first group could be able to segregate doxorubicin in subcellular compartments from which it could not reach its nuclear targets.
Fondation Bergonié, Bordeaux, France.
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D000818:Animals; D001254:Astrocytoma / Q000188:drug therapy / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004351:Drug Resistance; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D014227:Triazines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D010880:Piperidines; D014227:Triazines; C077022:S 9788; D004317:Doxorubicin