Clinical importance of P-glycoprotein-related resistance in leukemia and myelodysplastic syndromes — first experience with their reversal

Abstract

P-glycoprotein (P-gp) expression in mononuclear bone marrow cells was analyzed in 119 patients, including 60 with chronic myelogenous leukemia (CML), 48 with myelodysplastic syndromes (MDS), and 11 with acute myelogenous leukemia (AML). For P-gp measurement an immunocytological method using monoclonal antibodies C219, 4E3, and MRK 16 and the reverse transcription-polymerase chain reaction technique were applied. According to our results obtained in healthy volunteers using the immunocytological method, the limit for P-gp overexpression was set at > or = 10% P-gp-positive mononuclear bone marrow cells and at > or = 30% P-gp-positive mononuclear peripheral blood cells. All 42 CML patients in chronic phase had normal P-gp expression. P-gp overexpression was demonstrated in four of six patients in accelerated myelogenous blast cell phase and in four of 12 CML-BC patients. Of eight CML patients in blast crisis (BC) with normal P-gp expression, partial remission was achieved in three and minor response in five after prednisone/vindesine therapy. All four of the 12 CML-BC patients with P-gp overexpression did not respond to this therapy. Normal P-gp expression was seen in 41 (85.4%) of 48 untreated MDS patients. While P-gp overexpression did not develop during therapy in any of the myelodysplastic syndrome patients treated with low-dose ara-C alone, four of eight treated with low-dose ara-C plus GM-CSF and four of 11 treated with low-dose ara-C and IL-3 developed P-gp overexpression after therapy. Furthermore, 11 AML patients at primary diagnosis, including five AML patients with P-gp overexpression, who were treated with idarubicin, vepesid, and cytarabine V (ara-C) showed a complete remission. Additionally, one daunorubicin-cytarabine-pretreated refractory AML patient was treated with the oral form of the P-gp modulator drug dexniguldipine and achieved complete remission for a duration of 7 months. Our results suggest that in CML patients in BC, P-gp expression influences outcome after therapy. Further more, studies in a larger series of patients are necessary to prove the efficacy and toxicity of idarubicin/vepesid and cytardbine--or dexniguldipine-containing--therapy in relation to P-gp expression of AML patients.

Revisiting the ABCs of Multidrug Resistance in Cancer Chemotherapy

“…The expression of ABCB1 in all stages of CML can be quite variable. For example, it has been shown that ABCB1 expression can range from 0-100% in the chronic phase (CP) in CML patients [76,[162][163][164][165][166][167][168]. Several groups have reported that ABCB1 expression is higher in the blastic phase than the chronic phase [162,164,[167][168][169].…”

Cyclosporin increases cellular idarubicin and idarubicinol concentrations in relapsed or refractory AML mainly due to reduced systemic clearance

“…Previous reports also showed conflicting results between the functional assay and direct labeling with MoAbs. 9,11,55,56 All patients included in this trial were pretreated with an anthracycline containing regimen: six patients were treated with IDA and one patient with mitoxantrone. Currently, no conclusive data are available on Pgp and MRP1 expression on blasts of clinically resistant AML patients after pretreatment with IDA.…”

Correlation between the Type of BCR-ABL Transcripts and Blood Cell Counts in Chronic Myeloid Leukemia—A Possible Influence of MDR1 Gene Expression

“…14,16–20 Even less is known about the relationship of the MDR1 levels to clinical data at presentation in CML. 14 The association between the MDR1 levels and type of BCR-ABL transcripts to our knowledge has not been studied yet.…”