Influence of SDZ-PSC833 on daunorubicin intracellular accumulation in bone marrow specimens from patients with acute myeloid leukaemia.
The multidrug resistance (MDR) modulating activity of SDZ-PSC833 (PSC), a non-immunosuppressive cyclosporine analogue, was investigated and compared with cyclosporin A (CSA) in bone marrow clinical specimens from 45 patients with acute myeloid leukaemia (AML) taken at diagnosis, using double-labelling flow cytometry with simultaneous determination of P-glycoprotein (PGP) expression and intracellular daunorubicin fluorescence (IDF). On the basis of pre-clinical results in multidrug-resistant K562 leukaemic cells, concentrations leading to iso-effective complete restoration of IDF were used: 5 and 10 micromol/l, respectively for PSC and CSA. In the clinical specimens, PGP expression was correlated with a significant decrease in IDE PSC was found to be significantly more potent than CSA since it was found to induce a significant increase in IDF in a higher number of cases and to a higher extent than CSA. PGP-unrelated activity of PSC was also observed in specimens expressing no PGP but exhibiting low IDF, thus probably expressing alternative resistance mechanisms. The results confirm the potency of PSC as MDR-modulating agent in clinical AML specimens whose resistance pattern differed from that of highly resistant cell models and suggest that the activity of PSC is not limited to P-glycoprotein inhibition.
Merlin
J L
JL
Centre Alexis Vautrin, Laboratoire de Recherche en Oncologie, Vandoeuvre-Les-Nancy, France.
Guerci
A P
AP
Marchal
S
S
Bour
C
C
Colosetti
P
P
Kataki
A
A
Guerci
O
O
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000208:Acute Disease; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D001853:Bone Marrow / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D003630:Daunorubicin / Q000493:pharmacokinetics*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D016572:Cyclosporine; C070272:valspodar; D003630:Daunorubicin