P‐glycoprotein and multidrug resistance‐associated protein, but not lung resistance protein, lower the intracellular daunorubicin accumulation in acute myeloid leukaemic cells

Abstract

Summary. The in vitro intracellular daunorubicin accumulation (IDA) of blast cells from 69 patients with newly diagnosed acute myeloid leukaemia (AML) was correlated with the expression and functional activity of the multidrug resistance (MDR) proteins, P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP) and lung-resistance protein (LRP). An inverse and signi®cant association was found between IDA and Pgp-related ef¯ux activity (r À0´31, P 0´01) and also MRP (r À0´25, P 0´04) but not with LRP (r À0´13, P 0´28). Coexpression of the MDR proteins had an additive effect in further lowering of IDA levels, suggesting that the clinical MDR phenotype is dependent on the sum of multiple MDR factors available to the leukaemic cell. Thus, the median IDA of leukaemic cells without any MDR proteins was signi®cantly higher than that of blasts carrying two MDR proteins (0´466 vs. 0´296, P 0´046). Seven patients with no expression of Pgp, MRP and LRP still had low IDA levels, suggesting the presence of ef¯ux MDR mechanisms other than those studied. The relation of IDA to clinical parameters known to be associated with poor prognosis, such as age, secondary AML, karyotype, peripheral blood blast and CD34 counts, was also studied, but no signi®cance was found on multifactorial analysis. There was a non-signi®cant trend for earlier relapse in patients with low IDA levels (leukaemia-free survival of 16´3 months compared with 21´1 months in patients with high IDA levels). Our data suggest that, while the IDA assay is a quick and relatively easy test for the combined ef¯ux MDR phenotype, it is unable to detect other MDR mechanisms, such as LRP, which may be important to the clinical outcome of patients with AML.

Immunohistochemical Expression of Multidrug Resistance Proteins as a Predictor of Poor Response to Chemotherapy and Prognosis in Patients with Nodal Diffuse Large B-Cell Lymphoma

“…Izquierdo et al [11 ]examined expression of P-gp, MRP1, and LRP in 58 human cancer cell lines and found co-expression of two or three MDR proteins in 64% of the lines, which was associated with high levels of drug resistance. Borg et al [38]observed that co-expression of MDR proteins has an additive effect in the lowering of drug accumulation levels in leukemic cell lines. Co-expression of MDR proteins has been reported in multiple myeloma [39], AML [13], and soft tissue sarcoma [40].…”

Reduced effect of gemtuzumab ozogamicin (CMA-676) on P-glycoprotein and/or CD34-positive leukemia cells and its restoration by multidrug resistance modifiers

“…MRP, as well as P-gp, has been reported to be over-expressed on some leukemia cells and associated with lower intracellular drug accumulation in AML. 33 However, the impact of MRP on clinical outcomes in AML remains to be proven. Our data suggest that MRP is not associated with CMA-676 resistance in AML, but further investigations are required to clarify this association.…”

Functional characterization of minimal residual disease for P-glycoprotein and multidrug resistance protein activity in acute myeloid leukemia

“…Expression and function of Pgp in de novo AML patients has been shown to be an independent adverse prognostic factor for response and survival. [20][21][22][23][24][25][26] Furthermore, in some studies higher Pgp expression was found in refractory and relapsed AML. 22,24,27 The use of rhodamine123 as Pgp probe, combined with PSC833 as Pgp inhibitor in an accumulation assay represents a sensitive and reproducible functional assay in AML both in efflux 28 and accumulation 29,30 assay and is also applicable for frozen/thawed samples.…”

“…31 Apart from Pgp, MRP1 (further referred to as MRP) might contribute to the multidrug resistance (MDR) phenotype in AML. 24,25,[32][33][34][35][36] It has been shown that among others the combination of calcein-AM and probenecid can be used to detect MRP function. 37,38 To investigate the role of Pgp and MRP in drug resistance in AML, the most informative approach would be to functionally characterize MRD cells at different stages of disease of the patient.…”