Distribution and activity of doxorubicin combined with SDZ PSC 833 in mice with P388 and P388/DOX leukaemia.
SDZ PSC 833 (PSC 833) is a non-immunosuppressive analogue of cyclosporin A and is a potent modifier of P-glycoprotein (P-gp)-mediated multidrug resistance. The present study was undertaken to evaluate whether doxorubicin (DOX) pharmacokinetic and anti-tumour activity on P388- and P388/DOX-resistant leukaemia was modified by PSC 833 pretreatment. P388- or P388/DOX-bearing mice were given PSC 833 intraperitoneally 30 min before an intravenous injection of DOX. The levels of DOX were determined by a high-performance liquid chromatography method in leukaemic cells and in normal tissues (heart, lung, liver, small intestine, kidney and spleen). In all tissues, DOX concentrations were significantly increased in mice pretreated with PSC 833. The difference was greatest in P-gp-overexpressing P388/DOX cells, the DOX area under the curve being approximately seven times greater after PSC 833 and DOX than after DOX alone. In P388 cells the difference was approximately 2.5 times, as in the majority of normal tissues. As expected DOX levels in P388 cells were higher than in P388/DOX cells in mice treated with DOX alone, whereas after PSC 833 and DOX the levels of DOX were similar in the two leukaemic lines. In spite of this PSC 833 was unable to reverse the resistance to DOX of P388/DOX leukaemia in vivo, suggesting that mechanisms other than P-gp expression are responsible for resistance.
Colombo
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Laboratory of Cancer Chemotherapy, Mario Negri Institute for Pharmacological Research, Milan, Italy.
Gonzalez Paz
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D'Incalci
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D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000235:genetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015152:Blotting, Northern; D003524:Cyclosporins / Q000494:pharmacology*; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004347:Drug Interactions; D004351:Drug Resistance; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014018:Tissue Distribution
D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D003524:Cyclosporins; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C070272:valspodar