Decreased uptake of cyclosporin A by P-glycoprotein (Pgp) expressing CEM leukemic cells and restoration of normal retention by Pgp blockers.
The P-glycoprotein (Pgp) molecules which are expressed on multidrug resistant (MDR) tumor cells can efflux a variety of cytostatics. In both normal and tumoral epitheliums, Pgp molecules are selectively expressed on the apical surface of the epithelial cells. Such a distribution seems to be responsible for the transcellular transport of Pgp substrates, including cyclosporin A (CsA), from the basal to the apical side. Some normal lymphoid cells also express small amounts of Pgp molecules, for as yet unknown functions. Nevertheless, the sensitivity of their mitogen-induced proliferation to cytostatics, including doxorubicin and CsA, could be increased by the Pgp blockers. Using isotopically-labeled CsA and tumoral lymphoid cell lines, we now show a higher CsA retention in Pgp-lacking parental ('Par') cells than in Pgp-expressing MDR cells. The Pgp blockers can restore the CsA retention in the MDR cells to its level in the Par cells.
Didier
A
A
Laboratoire d'Immunologie, Strasbourg 1 University, Illkirch, France.
Wenger
J
J
Loor
F
F
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016572:Cyclosporine / Q000493:pharmacokinetics*; D003524:Cyclosporins / Q000494:pharmacology; D003630:Daunorubicin / Q000737:chemistry / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010456:Peptides, Cyclic / Q000494:pharmacology; D012235:Rhodamines / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D010456:Peptides, Cyclic; D012235:Rhodamines; C072534:SDZ 280 446; D014747:Vinblastine; D004317:Doxorubicin; D016572:Cyclosporine; D014700:Verapamil; C070272:valspodar; D003630:Daunorubicin