In vitro evaluation of chemosensitizers for clinical reversal of P-glycoprotein-associated Taxol resistance.
The purpose of this study was to estimate the potential usefulness of currently available chemosensitizers (CS) for clinical reversal of P-glycoprotein-mediated Taxol resistance. The 8226/DOX6 human myeloma cells were used to evaluate CS effects in serum-rich medium by means of the human tumor cloning assay. The 8226/DOX6 cells express low levels of P-glycoprotein as typically found in clinical cancer specimens and are approximately 40-fold resistant to Taxol when continuously exposed to the drug in serum-rich medium. The CS were used at maximum tolerated plasma levels (Cmax) and at the concentrations achieved in human plasma by oral administration (Coral). Of nine CS tested, cyclosporine A (CSA), verapamil (VER), quinidine (QD), and quinine (Q) were able to overcome Taxol resistance. QD and Q were effective at Coral, whereas CSA and VER required Cmax to significantly enhance Taxol cytotoxicity. The most potent agent was CSA, which increased sensitivity to Taxol by 8-, 12-, and 18-fold when used at concentrations of 1.0, 2.0, and 4.0 microM, respectively. At 5.0 microM, CSA was capable of fully normalizing Taxol sensitivity. On the basis of these data, infusional CSA might prove useful for clinical reversal of P-glycoprotein-associated Taxol resistance. It remains to be seen, however, whether the CSA concentrations needed to reverse Taxol resistance effectively can be safely achieved in human plasma when CSA is coadministered with Taxol.
Lehnert
M
M
Arizona Cancer Center, University of Arizona College of Medicine, Tucson.
Emerson
S
S
Dalton
W S
WS
de Giuli
R
R
Salmon
S E
SE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D004351:Drug Resistance; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D009101:Multiple Myeloma / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D011803:Quinine / Q000494:pharmacology; D014268:Trifluoperazine / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D014268:Trifluoperazine; D016572:Cyclosporine; D011803:Quinine; D014700:Verapamil; D017239:Paclitaxel