Influence of SDZ‐PSC833 on daunorubicin intracellular accumulation in bone marrow specimens from patients with acute myeloid leukaemia

Abstract

Summary. 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 mmol/l, respectively for PSC and CSA.In the clinical specimens, PGP expression was correlated with a significant decrease in IDF. 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.

CMC‐544 (inotuzumab ozogamicin) shows less effect on multidrug resistant cells: analyses in cell lines and cells from patients with B‐cell chronic lymphocytic leukaemia and lymphoma

“…P‐gp function was determined by measuring intracellular Rh123 accumulation and its enhancement by MDR modifiers, such as PSC833 (Novartis Pharma, Basel, Swizerland) or MS209 (Mitsui Phamaceuticals, Chiba, Japan), as previously described (Nakanishi et al , 1997; Merlin et al , 1998; Matsui et al , 2002; Takeshita et al , 2005).…”

Calcein assay for multidrug resistance reliably predicts therapy response and survival rate in acute myeloid leukaemia

“…Chemotherapy is the key choice of treatment in these diseases and therapy outcome is significantly affected by primary or secondary drug resistance, observed in many cases. Moreover, the recent clinical trials, involving the co‐application of drug resistance‐modulating agents (Kaye, 1998; Merlin et al , 1998; Advani et al , 1999), should be planned and performed on the basis of a proper diagnosis of the actual presence and form of MDR.…”

New drugs in the treatment of acute myeloid leukaemia

“…Th erefore, the development of P-gp modulators that block P-gp-mediated drug effl ux seems to be an attractive target to overcome drug resistance. Interesting results had been shown for PSC-883, a nonimmunosuppressive cyclosporine analogue, which induced a signifi cant increase in intracellular daunorubicin accumulation by the inhibition of P-gp function [6]. However, a clinical phase III trial comparing conventional chemotherapy with or without the MDR modulator PSC-833, showed no benefi t and had to be terminated early due to excess toxicity [7].…”