title: Cytotoxic effects of a doxorubicin-transferrin conjugate in multidrug-resistant KB cells.
abstract: Cancer chemotherapy is often limited by the emergence of multidrug-resistant tumor cells. Multidrug resistance (MDR) can be caused by amplification of the MDR genes and overexpression of the P-glycoprotein, which is capable of lowering intracellular drug concentrations. A doxorubicin-transferrin conjugate has been synthesized and exerts its cytotoxic effects through a transmembrane mechanism. We have examined the cytotoxicity of this conjugate and compared it with doxorubicin in sensitive (KB-3-1) and in multidrug-resistant KB cell lines (KB-8-5, KB-C1, and KB-V1). In the clonogenic assay, doxorubicin exhibited IC50 concentrations of 0.03 and 0.12 microM in the sensitive (KB-3-1) and resistant (KB-8-5) cell lines, respectively, whereas, doxorubicin-transferrin conjugate was more effective with IC50 concentrations of 0.006 and 0.028 microM, respectively. In highly multidrug-resistant KB-C1 and KB-V1 cells, doxorubicin up to 1 microM did not cause any cytotoxic effects, while the doxorubicin-transferrin conjugate inhibited colony formation of these cells with IC50 levels of 0.2 and 0.025 microM, respectively. These results demonstrate that doxorubicin-transferrin is effective against multidrug-resistant tumor cells.
authors.affiliation: Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Fritzer
authors.forename: T
authors.initials: T
authors.lastname: Szekeres
authors.forename: V
authors.initials: V
authors.lastname: Szüts
authors.forename: H N
authors.initials: HN
authors.lastname: Jarayam
authors.forename: H
authors.initials: H
authors.lastname: Goldenberg
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000633:toxicity*; D018432:Drug Resistance, Multiple; D015870:Gene Expression; D006801:Humans; D007624:KB Cells; D007700:Kinetics; D011990:Receptors, Transferrin / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014168:Transferrin / Q000031:analogs & derivatives / Q000378:metabolism*; D014410:Tumor Stem Cell Assay
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004273:DNA, Neoplasm; D011990:Receptors, Transferrin; D014168:Transferrin; D004317:Doxorubicin; D013936:Thymidine