TREATMENT OF THE P815 MURINE MASTOCYTOMA WITH CISPLATIN OR ETOPOSIDE UP-REGULATES CELL-SURFACE FAS (CD95) EXPRESSION AND INCREASES SENSITIVITY TO ANTI-FAS ANTIBODY-MEDIATED CYTOTOXICITY AND TO LYSIS BY ANTI-CD3-ACTIVATED KILLER-T CELLS

We have investigated the effect of pre-treatment with the anti cancer drugs cisplatin and etoposide on the susceptibility of P815 murine mas tocytoma cells to lysis by murine spleen-derived anti-CD3-activated ki ller-T (AK-T) cells. A 20 hr pre treatment with cisplatin (0.2-2 mu g/ ml) or etoposide (0.01-1 mu g/ml) rendered P815 cells significantly mo re sensitive to AK-T cell-mediated lysis in a 4 hr Cr-51-release assay than untreated control tumor cells. At lower concentrations, pre-trea tment with cisplatin or etoposide had no direct cytotoxic effects on P 815 tumor cells, as measured by the MTT assay. AK-T cell-mediated kill ing of P815 tumor cells pre-treated with 2 mu g/ml cisplatin or I mu g /ml etoposide was only partially inhibitable by the Ca2+ chelator EGTA , suggesting that the Ca2+-independent Fas (CD95)/Fas ligand cytolytic pathway of AK-T cells contributes to cytotoxicity. In comparison to u ntreated control P815 cells, 2 mu g/ml cisplatin-or I mu g/ml etoposid e-treated P815 cells exhibited increased expression of pas mRNA and ce ll-surface pas, which correlated with increased sensitivity to lysis b y AK-T cells. In addition, pre-treatment with cisplatin or etoposide c aused P815 tumor cells to become sensitive to the cytotoxic effects of anti-pas antibody in a 4 hr Cr-51-release assay. Taken together, our results demonstrate that short-term exposure to concentrations of cisp latin and etoposide in the low cytotoxic range and below up-regulates pas expression by P815 tumor cells, thereby facilitating cytotoxicity mediated through the Fas/Fas ligand cytolytic pathway. (C) 1997 Wiley- Liss, Inc.