title: Relationship between therapeutic efficacy of doxorubicin-transferrin conjugate and expression of P-glycoprotein in chronic erythromyeloblastoid leukemia cells sensitive and resistant to doxorubicin.
abstract: BACKGROUND
  Conjugation of anti-neoplastic agents with human proteins is a strategy to diminish the toxic side effects of anthracycline antibiotics. We have developed a novel doxorubicin-transferrin (DOX-TRF) conjugate aimed to direct anticancer drugs against therapeutic targets that display altered levels of expression in malignant versus normal cells. Our previous work has shown that the cellular bio-distribution of the conjugate is dependent on a dynamic balance between influx and efflux processes. Here, we set out to investigate whether P-glycoprotein (P-gp) expression may affect DOX-TRF conjugate-induced cellular drug accumulation and cytotoxicity.
  
  
  RESULTS
  All experiments were carried out on human erythromyeloblastoid cells exhibiting P-gp over-expression (K562/DOX) and its drug sensitive parental line (K562). MTT cytotoxicity, flow cytometry, fluorescence microscopy and RT-PCR assessments revealed that the investigated conjugate (DOX-TRF) possesses a greater cytotoxic potential than free DOX.
  
  
  CONCLUSIONS
  Our data suggest that the newly developed DOX-TRF conjugate is a less P-gp dependent substrate than free DOX and, consequently, may be used in a clinical setting to increase treatment efficacy in resistant human tumors.
authors.affiliation: Department of Thermobiology, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143 Street, 90-236, Lodz, Poland, szwedma@biol.uni.lodz.pl.
authors.forename: Marzena
authors.initials: M
authors.lastname: Szwed
authors.forename: Katarzyna D
authors.initials: KD
authors.lastname: Kania
authors.forename: Zofia
authors.initials: Z
authors.lastname: Jozwiak
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D014168:Transferrin / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014168:Transferrin; D004317:Doxorubicin