Potentiation of the reversal activity of SDZ PSC833 on multi-drug resistance by an anti-P-glycoprotein monoclonal antibody MRK-16.
SDZ PSC833 (PSC833), an analogue of cyclosporines, is one of the most potent modulators of multi-drug resistance (MDR). We previously reported that MRK-16, an anti-P-glycoprotein MAb, enhanced MDR reversal activity of cyclosporin A (CsA) through inhibition of P-glycoprotein-mediated CsA transport. We have examined here whether MRK-16 can enhance MDR reversal activity of PSC833. We found that MRK-16 potentiated the MDR reversal activity of PSC833, and of CsA, in MDR sublines of human myelocytic leukemia K562 and human ovarian cancer A2780 cells. Like MRK-16 combined with CsA, MRK-16 enhanced the effect of a sub-optimum dose of PSC833 on vincristine accumulation in MDR cells. However, MRK-16 could not increase cellular accumulation of PSC833 in MDR tumor cells, yet it could increase cellular accumulation of CsA. P-glycoprotein could not transport PSC833 but could transport CsA. Our results indicate that MRK-16 potentiates the MDR reversal activity of both PSC833 and CsA, yet also suggest that the molecular mechanism of the potentiation differs between the two substances.
Naito
M
M
Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
Watanabe
T
T
Tsuge
H
H
Koyama
T
T
Oh-hara
T
T
Tsuruo
T
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000276:immunology*; D000345:Affinity Labels; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000493:pharmacokinetics / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000493:pharmacokinetics / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000911:Antibodies, Monoclonal; D003524:Cyclosporins; D014750:Vincristine; D016572:Cyclosporine; C070272:valspodar