title: The strong in vivo anti-tumor effect of the UIC2 monoclonal antibody is the combined result of Pgp inhibition and antibody dependent cell-mediated cytotoxicity.
abstract: P-glycoprotein (Pgp) extrudes a large variety of chemotherapeutic drugs from the cells, causing multidrug resistance (MDR). The UIC2 monoclonal antibody recognizes human Pgp and inhibits its drug transport activity. However, this inhibition is partial, since UIC2 binds only to 10-40% of cell surface Pgps, while the rest becomes accessible to this antibody only in the presence of certain substrates or modulators (e.g. cyclosporine A (CsA)). The combined addition of UIC2 and 10 times lower concentrations of CsA than what is necessary for Pgp inhibition when the modulator is applied alone, decreased the EC50 of doxorubicin (DOX) in KB-V1 (Pgp+) cells in vitro almost to the level of KB-3-1 (Pgp-) cells. At the same time, UIC2 alone did not affect the EC50 value of DOX significantly. In xenotransplanted severe combined immunodeficient (SCID) mice co-treated with DOX, UIC2 and CsA, the average weight of Pgp+ tumors was only ∼10% of the untreated control and in 52% of these animals we could not detect tumors at all, while DOX treatment alone did not decrease the weight of Pgp+ tumors. These data were confirmed by visualizing the tumors in vivo by positron emission tomography (PET) based on their increased 18FDG accumulation. Unexpectedly, UIC2+DOX treatment also decreased the size of tumors compared to the DOX only treated animals, as opposed to the results of our in vitro cytotoxicity assays, suggesting that immunological factors are also involved in the antitumor effect of in vivo UIC2 treatment. Since UIC2 binding itself did not affect the viability of Pgp expressing cells, but it triggered in vitro cell killing by peripheral blood mononuclear cells (PBMCs), it is concluded that the impressive in vivo anti-tumor effect of the DOX-UIC2-CsA treatment is the combined result of Pgp inhibition and antibody dependent cell-mediated cytotoxicity (ADCC).
authors.affiliation: Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Szalóki
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Zoárd T
authors.initials: ZT
authors.lastname: Krasznai
authors.affiliation: Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Tóth
authors.affiliation: Department of Preventive Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Laura
authors.initials: L
authors.lastname: Vízkeleti
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Attila G
authors.initials: AG
authors.lastname: Szöllősi
authors.affiliation: Department of Nuclear Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Trencsényi
authors.affiliation: Department of Nuclear Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Imre
authors.initials: I
authors.lastname: Lajtos
authors.affiliation: Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; Department of Surgery and Operative Techniques, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Juhász
authors.affiliation: Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Krasznai
authors.affiliation: Department of Nuclear Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Teréz
authors.initials: T
authors.lastname: Márián
authors.affiliation: Department of Preventive Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Margit
authors.initials: M
authors.lastname: Balázs
authors.affiliation: Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Szabó
authors.affiliation: Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Goda
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D006801:Humans; D016513:Mice, SCID
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004317:Doxorubicin; D016572:Cyclosporine