Overexpression of the mdr1 gene in blast cells from patients with acute myelocytic leukemia is associated with decreased anthracycline accumulation that can be restored by cyclosporin-A.
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 mdr1 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 P-glycoprotein inhibitors could increase the daunorubicin (DNR) accumulation in acute myelocytic leukemia (AML) cells, overexpressing the mdr1 gene. Using dot blot analysis with an mdr1-specific cDNA probe, we identified leukemic cell samples, obtained from chemotherapy-resistant AML patients, that had relatively high levels of mdr1 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 mdr1 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.
Nooter
K
K
Radiobiological Institute TNO, Rijswijk, The Netherlands.
Sonneveld
P
P
Oostrum
R
R
Herweijer
H
H
Hagenbeek
T
T
Valerio
D
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000293:Adolescent; D000328:Adult; D000368:Aged; D003524:Cyclosporins / Q000494:pharmacology*; D003630:Daunorubicin / Q000493:pharmacokinetics*; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D008562:Membrane Glycoproteins; D014700:Verapamil; D003630:Daunorubicin