Cyclosporine inhibition of P-glycoprotein in chronic myeloid leukemia blast phase.
Chronic myeloid leukemia blast phase (CML-BP) cells commonly express the multidrug transporter, P-glycoprotein (Pgp). To determine whether Pgp inhibition improves treatment outcome in CML-BP, the Southwest Oncology Group performed a randomized, controlled trial testing the benefit of the Pgp modulator, cyclosporin A (CsA). Seventy-three eligible patients were assigned to treatment with cytarabine and infusional daunorubicin with or without intravenous CsA. Treatment with CsA yielded no improvement in treatment outcome as measured by the frequency of induction resistance (68% vs 53%), rate of complete remission or restored chronic phase (CR/CP, 8% vs 30%), and survival (3 vs 5 months). Blast expression of Pgp (63%) and LRP (71%) was common, whereas only Pgp adversely impacted the rate of CR/CP (P =.025). We conclude that Pgp has prognostic relevance in CML-BP but that the modulation of Pgp function with CsA as applied in this trial is ineffective.
List
Alan F
AF
Arizona Cancer Center, Tucson, USA.
Kopecky
Kenneth J
KJ
Willman
Cheryl L
CL
Head
David R
DR
Slovak
Marilyn L
ML
Douer
Dan
D
Dakhil
Shaker R
SR
Appelbaum
Frederick R
FR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012074:Remission Induction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D016572:Cyclosporine