Expression of P-glycoprotein on normal lymphocytes: enhancement of the doxorubicin-sensitivity of concanavalin A-responding mouse spleen cells by P-glycoprotein blockers.
The in vitro proliferative response of mouse spleen cells (SC) to the T-cell mitogen, concanavalin A (ConA), displays a doxorubicin (DOX)-resistant component. This T-cell proliferative response displays a much higher DOX sensitivity in the presence of novel potent inhibitors of P-glycoprotein (Pgp)-mediated multidrug resistance (MDR), the cyclosporin (Cs) derivative, SDZ PSC 833, and the semi-synthetic cyclopeptolide, SDZ 280-446. Another resistance modulator, verapamil, might share this property, but its detection was impaired by the intrinsic toxicity of this calcium channel blocker for T-cell proliferation. A CD8+ cell-depleted SC suspension displayed a higher sensitivity to DOX alone, as well as a different sensitivity profile to SDZ 280-446. The CD8+ cells that are sensitized to DOX by the resistance modulating agents (RMA) might correspond to a formerly described T-cell subpopulation with the MDR phenotype, which seems to be essentially constituted of CD8+ (cytotoxic) T cells. Our results may open the way to a novel form of immunomodulation combining classical antineoplastic agents with Pgp-blocking Cs analogs (even non-immunosuppressive ones), which may be particularly useful when treating acute graft rejection.
Pourtier-Manzanedo
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Laboratoire d'Immunologie, Université de Strasbourg, France.
Didier
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Loor
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D016827:CD8 Antigens / Q000032:analysis; D003208:Concanavalin A / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D004357:Drug Synergism; D005260:Female; D008213:Lymphocyte Activation / Q000187:drug effects; D008212:Lymphocyte Depletion; D008214:Lymphocytes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D010456:Peptides, Cyclic / Q000494:pharmacology; D013154:Spleen / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016827:CD8 Antigens; D003524:Cyclosporins; D008562:Membrane Glycoproteins; D010456:Peptides, Cyclic; D003208:Concanavalin A; C072534:SDZ 280 446; D004317:Doxorubicin; D014700:Verapamil; C070272:valspodar