P-glycoprotein-mediated multidrug resistance and lymphokine-activated killer cell susceptibility in ovarian carcinoma.

Abstract

The sensitivity of tumor cells to lysis by natural killer (NK) and interleukin-2 (IL-2)-activated killer (LAK) cells was studied in three ovarian carcinoma cell lines (2780.9S, SKOV-3, and CHOAUXB1), four multidrug-resistant (MDR) variants, and a melphalan-resistant line. The antitumor activity of LAK cells was evaluated both by 51Cr release and by conjugate formation assays. Four of four P-glycoprotein-positive (P-gp+) MDR ovarian carcinoma cell line variants were lysed by human LAK cells to a greater extent than were their drug-sensitive counterparts. In contrast, a melphalan-resistant ovarian carcinoma cell line that does not overexpress P-gp (P-gp-) did not exhibit an increased susceptibility to LAK cells relative to its parental cell line. Two of the four P-gp+ MDR ovarian carcinoma cell line variants were tested for human NK cell susceptibility and this was found to be unchanged or decreased. The P-gp+ MDR ovarian carcinoma cell line 2780.AD645 showed a higher frequency of tumor cell binding to LAK cells than did the drug-sensitive parental line. A monoclonal antibody (mAb) against a cell surface epitope of P-gp, MRK16, used at 1 microgram/ml, enhanced the LAK susceptibility of P-gp+ MDR ovarian carcinoma cell lines. However, when incubation with 10 micrograms/ml MRK-16 antibody (Ab) was followed by 12.5 micrograms/ml F(ab')2 goat anti-mouse (GAM) immunoglobulin (Ig), the increased LAK susceptibility of P-gp+ MDR cell lines was inhibited. These data strongly suggest that P-glycoprotein-positive MDR ovarian carcinoma cells not only are targets for LAK cells, but are more sensitive than their drug-sensitive parental lines. This is in contrast to their susceptibility to NK cells, which is low to start with and remains unchanged or even decreased in MDR cells. It is postulated here that P-gp or associated changes result in a greater frequency of effector-target cell binding, leading to increased LAK cell cytotoxicity.