INFLUENCE OF SDZ-PSC833 ON DAUNORUBICIN INTRACELLULAR ACCUMULATION INBONE-MARROW SPECIMENS FROM PATIENTS WITH ACUTE MYELOID-LEUKEMIA

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 fr om 45 patients with acute myeloid leukaemia (AML) taken at diagnosis, using double-labelling now cytometry with simultaneous determination o f P-glycoprotein (PGP) expression and intracellular daunorubicin fluor escence (IDF). On the basis of pre-clinical results in multidrug-resis tant K562 leukaemic cells, concentrations leading to iso-effective com plete restoration of IDF were used: 5 and 10 mu mol/l, respectively fo r PSC and CSA. In the clinical specimens, PGP expression was correlate d with a significant decrease in IDE PSC was found to be significantly more potent than CSA since it was found to induce a significant incre ase 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 express ing no PGP but exhibiting low IDE thus probably expressing alternative resistance mechanisms. The results confirm the potency of PSC as MDR- modulating agent in clinical AML specimens whose resistance pattern di ffered from that of highly resistant cell models and suggest that the activity of PSC is not limited to P-glycoprotein inhibition.