title: Comparative evaluation of S9788, verapamil, and cyclosporine A in K562 human leukemia cell lines and in P-glycoprotein-expressing samples from patients with hematologic malignancies.
abstract: The activity of S9788, recently synthetized as a modulator of multidrug resistance (MDR), was compared with verapamil and cyclosporine A in normal sensitive and MDR K562 cell lines, then in samples from 33 patients with hematological malignancies, using flow cytometry with simultaneous detection of P-glycoprotein and determination of intracellular daunorubicin fluorescence. This technique was compared and correlated with a tritiated daunorubicin accumulation method. In K562 cell lines, S9788 exhibited a significantly higher reversing activity than verapamil and cyclosporine A, and allowed a complete restoration of the accumulation of daunorubicin when used at 5 mumol/L. In the clinical samples, the three compounds were evaluated at equimolar concentration (5 mumol/L) using concomitant exposure to daunorubicin and to the reversing agent. In P-glycoprotein-negative samples, no significant effect on intracellular daunorubicin fluorescence of any of the reversing agents was noted. In the 15 P-glycoprotein-positive samples, a significant increase in daunorubicin fluorescence, by at least one reversing agent, was seen in 10 cases, among which S9788 reversing activity was higher than that of the two other agents in seven cases. Complete reversal was only achieved in one case with S9788.
authors.affiliation: Centre Alexis Vautrin, Vandoeuvre-Nancy, France.
authors.forename: J L
authors.initials: JL
authors.lastname: Merlin
authors.forename: A
authors.initials: A
authors.lastname: Guerci
authors.forename: S
authors.initials: S
authors.lastname: Marchal
authors.forename: N
authors.initials: N
authors.lastname: Missoum
authors.forename: C
authors.initials: C
authors.lastname: Ramacci
authors.forename: J C
authors.initials: JC
authors.lastname: Humbert
authors.forename: T
authors.initials: T
authors.lastname: Tsuruo
authors.forename: O
authors.initials: O
authors.lastname: Guerci
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000032:analysis*; D016572:Cyclosporine / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis*; D008875:Middle Aged; D010880:Piperidines / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D010880:Piperidines; D014227:Triazines; C077022:S 9788; D004317:Doxorubicin; D016572:Cyclosporine; D014700:Verapamil