M‐CSF gene transduction in multidrug‐resistant human cancer cells to enhance anti‐P‐glycoprotein antibody‐dependent macrophage‐mediated cytotoxicity

Abstract

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 (AD 10) 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‐AD 10 cells exhibited higher ADCC activity than untreated monocytes against MDRI‐positive cancer cells. This effect of the supernatant of AD 10 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.