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Evidence of a role for functional heterogeneity in multidrug resistance transporters in clinical trials of P‐glycoprotein modulation in acute myeloid leukemia
Author(s) -
Marcelletti John F.,
Sikic Branimir I.,
Cripe Larry D.,
Paietta Elisabeth
Publication year - 2019
Publication title -
cytometry part b: clinical cytometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.646
H-Index - 61
eISSN - 1552-4957
pISSN - 1552-4949
DOI - 10.1002/cyto.b.21737
Subject(s) - efflux , p glycoprotein , myeloid leukemia , bioassay , multiple drug resistance , pharmacology , biology , flow cytometry , myeloid , drug resistance , medicine , immunology , microbiology and biotechnology , biochemistry , genetics
Background Multidrug resistance (MDR) transporter proteins such as P‐glycoprotein (P‐gp) efflux a variety of chemotherapeutic drugs from acute myeloid leukemia (AML) blasts leading to clinical drug resistance. Methods This study examined heterogeneity of MDR functional efflux by AML blasts using two flow cytometry bioassays. Bone marrow specimens ( N = 50) from elderly patients with newly diagnosed AML were analyzed for CD34+ blasts with MDR efflux function. Efflux was measured with a fluorescent dye (DiOC 2 ) as a surrogate for oncology drugs that are substrates for MDR efflux. P‐gp‐mediated efflux was differentiated from non‐P‐gp MDR activities using zosuquidar, a highly selective P‐gp modulator. The bioassays included a zosuquidar‐dependent DiOC 2 accumulation bioassay that measured only P‐gp. The second method, termed the efflux bioassay, could detect P‐gp and other non‐P‐gp efflux depending on bioassay culture conditions. Results Sixty‐two percent of the specimens were considered positive for blasts with P‐gp function, and 26% of such P‐gp‐positive specimens also exhibited zosuquidar‐resistant (i.e., non‐P‐gp) MDR efflux activity; 37% of P‐gp‐negative AML blast specimens displayed zosuquidar‐resistant MDR function in the efflux bioassay. Conclusions These results confirm the heterogeneous nature of MDR efflux pumps in AML blasts, and provide support for the hypothesis that non‐P‐gp MDR contributed to negative results with zosuquidar in AML trials like ECOG‐ACRIN E3999. © 2018 International Clinical Cytometry Society