Document 0529
 DOCN  M9650529
 TI    Decreased potency of MDR-modulators under serum conditions determined by
       a functional assay.
 DT    9605
 AU    Ludescher C; Eisterer W; Hilbe W; Hofmann J; Thaler J; Department of
       Internal Medicine, University of Innsbruck,; Austria.
 SO    Br J Haematol. 1995 Nov;91(3):652-7. Unique Identifier : AIDSLINE
       MED/96048907
 AB    A variety of agents are capable of overcoming P-glycoprotein-mediated
       multidrug resistance (MDR) in vitro. However, the clinical potential of
       these compounds is often limited due to high plasma protein binding. We
       compared the efficacy of several MDR-reversing compounds in serum-free
       culture medium and under serum conditions by means of a functional
       assay. Using flow cytometry the efflux of the fluorescent dye rhodamine
       123 (Rh123) was measured from normal peripheral blood CD8+ T-lymphocytes
       which express low levels of P-glycoprotein. Inhibition of Rh123 efflux
       by R-verapamil, dexnigludipine-HCl, cyclosporin A, SDZ PSC833 and the
       protein kinase C (PKC) inhibitor CGP 41251 was determined in serum-free
       medium and in serum at concentrations from 0.1 to 50 mumol/l. With the
       exception of SDZ PSC833 all MDR modulators showed an insufficient or
       suboptimal modulation of P-glycoprotein under serum conditions at
       concentrations achievable in vivo. The highest potency under serum
       conditions demonstrated SDZ PSC833: even at a concentration of 0.5
       mumol/l a sufficient inhibitory effect was observed. Subsequently this
       approach was applied to patients suffering from B-cell chronic
       lymphocytic leukaemia (B-CLL; n = 3) and acute myeloid leukaemia (AML; n
       = 2) which were positive in the Rh123 efflux assay. As for normal CD8+
       T-lymphocytes, much higher drug concentrations were required under serum
       conditions to effectively inhibit Rh123 efflux from the leukaemic cells.
       Thus the interpretation of results of clinical 'modulator' trials should
       consider the decreased bioavailability of MDR-reversing agents.
 DE    Acute Disease  Antimetabolites, Antineoplastic/*METABOLISM
       Antineoplastic Agents/PHARMACOLOGY  Cyclosporine/PHARMACOLOGY
       CD8-Positive T-Lymphocytes/*METABOLISM  Dihydropyridines/PHARMACOLOGY
       Dose-Response Relationship, Drug  *Drug Resistance, Multiple  Flow
       Cytometry  Human  Leukemia, B-Cell, Chronic/METABOLISM  Leukemia,
       Myeloid/METABOLISM  P-Glycoprotein/PHARMACOLOGY  Rhodamines/*METABOLISM
       Verapamil/PHARMACOLOGY  JOURNAL ARTICLE

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