title: Comparison of P-glycoprotein expression and function with in vitro sensitivity to anthracyclines in AML.
abstract: The importance of P-glycoprotein (P-gp) in AML has been well documented. Resistance to the anthracyclines can be overcome by several agents including Cyclosporin A (CsA), PSC833 and GF120918. We describe an investigation into the expression, using MRK16 and UIC2, and function of P-gp using daunorubicin with and without modulators by flow cytometric analysis on previously frozen blast cells from 27 patients with primary or secondary AML. We compared this with the in vitro chemosensitivity, using the MTT assay, of fresh blast cells from the same patients. Whilst we found a correlation between P-gp function using CsA and GF120918 and expression using MRK16 (p < 0.05) and (p < 0.02) respectively, we were unable to find any overall correlation between expression and function of P-gp with either in vitro sensitivity to the anthracyclines, previous treatment, or 1 degree or 2 degrees disease. However it was possible to identify individual patients whose cells exhibited P-gp expression and function teamed with in vitro resistance to, and modification of, the anthracyclines. Furthermore, it is possible to identify which modulator had the greatest effect. The fact that we obtained higher indications of resistance reversal using the MTT assay along with finding P-gp expression and function in patients sensitive to the anthracyclines, suggests studies of P-gp should be teemed with chemosensitivity testing to identify specific patients who will benefit.
authors.affiliation: Haematology Research Department, Pembury Hospital, Kent, United Kingdom.
authors.forename: A W
authors.initials: AW
authors.lastname: Elgie
authors.forename: J M
authors.initials: JM
authors.lastname: Sargent
authors.forename: C J
authors.initials: CJ
authors.lastname: Williamson
authors.forename: G M
authors.initials: GM
authors.lastname: Lewandowicz
authors.forename: C G
authors.initials: CG
authors.lastname: Taylor
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism*; D000166:Acridines / Q000633:toxicity; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001752:Blast Crisis / Q000473:pathology; D001853:Bone Marrow / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D003630:Daunorubicin / Q000633:toxicity*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007546:Isoquinolines / Q000633:toxicity; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000473:pathology*; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000473:pathology*; D012008:Recurrence; D044005:Tetrahydroisoquinolines; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000903:Antibiotics, Antineoplastic; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D016572:Cyclosporine; C083501:Elacridar; D003630:Daunorubicin