In vitro effect of P-glycoprotein (P-gp) modulators on drug sensitivity of leukemic progenitors (CFU-L) in acute myelogenous leukemia (AML).
Cyclosporine A (CyA), a potent reversant of multidrug resistance (mdr), was studied for its effects on the sensitivity of leukemic progenitors (leukemia colony-forming units, CFU-L) to daunorubicin (DNR) and mitoxantrone. CyA was first compared to verapamil and cefoperazone for reversion of mdr in the mdr1+ cell line K562/DOX. A dramatic increase of sensitivity to 10(-6) M DNR was noted with CyA (0.5 and 1 microgram/ml) and verapamil (1 and 5 micrograms/ml), but not for cefoperazone (0.3 and 0.6 mg/ml). The sensitivity of K562/DOX to 10(-6) M mitoxantrone was also slightly enhanced by CyA. The change in CFU-L drug sensitivity in the presence of CyA was then tested in 12 relapsing/resisting patients and in 3 untreated patients with acute myelogenous leukemia (AML). No change in CFU-L sensitivity to DNR was noted, despite the presence of a subset of P-glycoprotein positive (P-gp+) cells in three out of the ten evaluable cases. Among the six evaluable cases tested with mitoxantrone and CyA, an increase of 50% in CFU-L sensitivity to mitoxantrone was noted in one (of three) P-gp+ patient. These data suggest that the CFU-L in AML rarely expressed the P-gp and that other mechanisms of drug resistance could be involved in AML.
Cell Kinetic and Cell Cultures Laboratory, Hematology Department, Hôtel-Dieu, Paris, France.
J P
JP
Marie
C
C
Helou
D
D
Thevenin
A
A
Delmer
R
R
Zittoun
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000328:Adult; D002438:Cefoperazone / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D008942:Mitoxantrone / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D002438:Cefoperazone; D016572:Cyclosporine; D008942:Mitoxantrone; D014700:Verapamil; D003630:Daunorubicin