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Overexpression of the MDRL gene in blast cells from patients with acute myelocytic leukemia is associated with decreased anthracycline accumulation that can be restored by cyclosporin‐A
Author(s) -
Nooter Kees,
Sonneveld Pieter,
Oostrum Robert,
Herweijer Hans,
Hagenbeek Ton,
Valerio Dinko
Publication year - 1990
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910450210
Subject(s) - daunorubicin , p glycoprotein , efflux , flow cytometry , anthracycline , multiple drug resistance , leukemia , cell culture , pharmacology , biology , drug resistance , microbiology and biotechnology , k562 cells , in vitro , cancer research , immunology , biochemistry , cancer , genetics , breast cancer
Typical multi‐drug resistance (MDR) in human and animal cell lines is caused by overactivity of a unidirectional drug efflux pump. This pump is composed of a 170‐kDa transmembrane glycoprotein (P‐glycoprotein) that is encoded by the so‐called mdrl gene. The functionally relevant characteristic of MDR cells is a defect in drug accumulation that can be restored by agents which inhibit the P‐glycoprotein pump. The purpose of our study was to find out whether Pglycoprotein inhibitors could increase the daunorubicin (DNR) accumulation in acute myelocytic leukemia (AML) cells, overexpressing the mdrl gene. Using dot blot analysis with an mdrl ‐specific cDNA probe, we identified leukemic cell samples, obtained from chemotherapy‐resistant AML patients, that had relatively high levels of mdrl expression. These leukemic cells showed a reduced ability to accumulate DNR in vitro , as quantitated by flow cytometry. Addition of cyclosporin‐A (Cy‐A), a drug known to inhibit the P‐glycoprotein pump, to the incubation medium resulted in an increase (up to 60%) in steady‐state drug uptake by the leukemic cells. The degree of Cy‐A‐induced increase in drug accumulation in the leukemic cells correlated approximately with the level of overexpression of the mdrl gene. Our data indicate that Cy‐A is a good candidate for combination chemotherapy with cytotoxic drugs in clinical trials, aimed at the treatment of drug resistance in AML.