M-CSF gene transduction in multidrug-resistant human cancer cells to enhance anti-P-glycoprotein antibody-dependent macrophage-mediated cytotoxicity.
A human macrophage-colony-stimulating-factor (M-CSF) gene inserted into an expression vector (pRc/CMV-MCSF) was transfected into multidrug-resistant (MDR) human ovarian cancer cells (AD10) to induce secretion of human M-CSF into the medium. The M-CSF level in the culture medium of the transfected cells reached 100 ng/ml after 7 days, and the ability of the cells to secrete M-CSF was stable for at least 3 months. Transfection of the M-CSF gene did not result in any change in expression of MDRI (P-glycoprotein), proliferation or chemosensitivity of the cells from those of the parent cells. There was also no difference between the transfected and the parent cells in susceptibility to NK cell- or interleukin-2-activated killer-cell-mediated cytotoxicity. Human blood monocytes that had been incubated for 4 days in medium with the culture supernatant of MH-AD10 cells exhibited higher ADCC activity than untreated monocytes against MDRI-positive cancer cells. This effect of the supernatant of AD10 cells was completely abolished by its treatment with a monoclonal anti-M-CSF antibody (MAb). When transfected human MDR cells were injected into nude mice, an inverse correlation was seen between the ability of the cells to produce M-CSF and their tumorigenicity. Thus, gene modification of MDR cancer cells seems hopeful as a therapeutic method for enhancing anti-MDRI-MAb-dependent macrophage-mediated cytotoxicity against human MDR cancer cells.
Heike
Y
Y
Third Department of Internal Medicine, University of Tokushima School of Medicine, Japan.
Sone
S
S
Yano
S
S
Seimiya
H
H
Tsuruo
T
T
Ogura
T
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics* / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology*; D002455:Cell Division; D002478:Cells, Cultured; D004351:Drug Resistance / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics*; D008264:Macrophages / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D009000:Monocytes / Q000276:immunology; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D016173:Macrophage Colony-Stimulating Factor