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 spleen-derived anti-CD3-activated killer-T (AK-T) cells. A 20 hr pre-treatment with cisplatin (0.2-2 microg/ml) or etoposide (0.01-1 microg/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 microg/ml cisplatin or 1 microg/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 P815 cells, 2 microg/ml cisplatin- or 1 microg/ml etoposide-treated P815 cells exhibited increased expression of Fas mRNA and 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.
Williams
B A
BA
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
Makrigiannis
A P
AP
Blay
J
J
Hoskin
D W
DW
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology*; D002945:Cisplatin / Q000627:therapeutic use; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000627:therapeutic use; D016219:Immunotherapy, Adoptive / Q000379:methods*; D015979:Killer Cells, Lymphokine-Activated; D008297:Male; D012515:Mast-Cell Sarcoma / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D015854:Up-Regulation; D019014:fas Receptor / Q000276:immunology* / Q000378:metabolism*
D000906:Antibodies; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D017252:CD3 Complex; D019014:fas Receptor; D005047:Etoposide; D002945:Cisplatin