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

Int J Cancer. 1997 Nov 4;73(3):416-23. doi: 10.1002/(sici)1097-0215(19971104)73:3<416::aid-ijc17>3.0.co;2-a.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / therapeutic use*
  • Antigens, Neoplasm / immunology*
  • Antigens, Neoplasm / metabolism*
  • Antineoplastic Agents / therapeutic use*
  • CD3 Complex / immunology*
  • Cisplatin / therapeutic use
  • Combined Modality Therapy
  • Dose-Response Relationship, Drug
  • Etoposide / therapeutic use
  • Immunotherapy, Adoptive / methods*
  • Killer Cells, Lymphokine-Activated*
  • Male
  • Mast-Cell Sarcoma / immunology*
  • Mast-Cell Sarcoma / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Up-Regulation
  • fas Receptor / immunology*
  • fas Receptor / metabolism*

Substances

  • Antibodies
  • Antigens, Neoplasm
  • Antineoplastic Agents
  • CD3 Complex
  • fas Receptor
  • Etoposide
  • Cisplatin