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 mastocytoma cells to lysis by murine spleenderived anti-CD3-activated killer- T (AK-T) cells. A 20 hr pre-treatment with cisplatin (0.2-2 μg/ml) or etoposide (0.01-1 μg/ml) rendered P815 cells significantly more sensitive to AK-T cell-mediated lysis in a 4 hr ⁵¹Cr-release assay than untreated control tumor cells. At lower concentrations, pre-treatment with cisplatin or etoposide had no direct cytotoxic effects on P815 tumor cells, as measured by the MTT assay. AK-T cell-mediated killing of P815 tumor cells pre-treated with 2 μg/ml cisplatin or I μg/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 untreated control P81S cells, 2 μg/ml cisplatin- or I μg/ml etoposide-treated P815 cells exhibited increased expression of Fas mRNA ancl cell-surface Fas, which correlated with increased sensitivity to lysis by AK-T cells. In addition, pre-treatment with cisplatin or etoposide caused P815 tumor cells to become sensitive to the cytotoxic effects of anti-Fas antibody in a 4 hr ⁵¹Cr-release assay. Taken together, our results demonstrate that short-term exposure to concentrations of cisplatin and etoposide in the low cytotoxic range and below up-regulates Fas expression by P815 tumor cells, thereby facilitating cytotoxicity mediated through the Fas/ Fas ligand cytolytic pathway.