title: Overexpression of lung-resistance protein and increased P-glycoprotein function in acute myeloid leukaemia cells predict a poor response to chemotherapy and reduced patient survival.
abstract: We investigated the role of the drug resistance-related proteins LRP, MRP and Pgp and the apoptotic suppressor, bcl-2, in relation to other clinical characteristics, with respect to response and survival in 91 patients with newly diagnosed AML, treated with standard chemotherapy. Multivariate analysis showed that poor response to chemotherapy was associated with increasing age (P=0.0004), LRP expression (P=0.0001) and Pgp function (P=0.015). The significant predictors of both leukaemia-free survival (LFS) and overall survival (OS) were LRP (LFS, P=0.01; OS, P=0.0001), Pgp function (LFS, P=0.0001; OS, P=0.0003) and cytogenetic abnormalities (LFS, P=0.0001; OS. P=0.0005). Patients with the lowest expression of LRP and Pgp function and favourable karyotype (group I) had an LFS of 30.2 months compared to 8 5 months in the group with the highest expression of LRP and Pgp and poor prognosis karyotype (group III, P=0.002). OS decreased from 75.4 months in group I to 7.9 months in group III patients (P <0.0001). Neither MRP nor bcl-2 were significantly associated with chemotherapy response and survival. Correlations were found between increasing expression of LRP and older age (P=0.05) and an unfavourable karyotype (P=0.005), but these variables were independent of each other in analysis of treatment response and patient survival. Our findings suggest that both LRP and Pgp are clinically relevant drug-resistance proteins and it may be necessary to modulate both LRP and Pgp functions in order to reverse the multidrug resistance phenotype in AML.
authors.affiliation: University Department of Clinical Haematology, Manchester Royal Infirmary, UK.
authors.forename: A G
authors.initials: AG
authors.lastname: Borg
authors.forename: R
authors.initials: R
authors.lastname: Burgess
authors.forename: L M
authors.initials: LM
authors.lastname: Green
authors.forename: R J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: J A
authors.initials: JA
authors.lastname: Yin
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D018952:Antigens, CD34 / Q000378:metabolism; D018572:Disease-Free Survival; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D011379:Prognosis; D012189:Retrospective Studies; D020394:Vault Ribonucleoprotein Particles / Q000378:metabolism*; D000099187:Major Vault Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018952:Antigens, CD34; D009363:Neoplasm Proteins; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein