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

• Published in: International journal of cancer 1997-11, Vol.73 (3), p.416-423
• Main Authors: Williams, Brent A., Makrigiannis, Andrew P., Blay, Jonathan, Hoskin, David W.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - therapeutic use; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Biological and medical sciences; CD3 Complex - immunology; Cisplatin - therapeutic use; Combined Modality Therapy; Dose-Response Relationship, Drug; Etoposide - therapeutic use; fas Receptor - immunology; fas Receptor - metabolism; General aspects; Immunotherapy, Adoptive - methods; Killer Cells, Lymphokine-Activated; Male; Mast-Cell Sarcoma - immunology; Mast-Cell Sarcoma - therapy; Medical sciences; Mice; Mice, Inbred C57BL; Pharmacology. Drug treatments; Up-Regulation
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/(SICI)1097-0215(19971104)73:3<416::AID-IJC17>3.0.CO;2-A

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 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 1 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 P815 cells, 2 μg/ml cisplatin– or 1 μg/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. Int. J. Cancer 73:416–423, 1997. © 1997 Wiley‐Liss, Inc.