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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.

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.

journal_name

Int J Cancer

journal_title

International journal of cancer

authors

Williams BA,Makrigiannis AP,Blay J,Hoskin DW

doi

10.1002/(sici)1097-0215(19971104)73:3<416::aid-ijc

subject

Has Abstract

pub_date

1997-11-04 00:00:00

pages

416-23

issue

eissn

0020-7136

issn

1097-0215

pii

10.1002/(SICI)1097-0215(19971104)73:3<416::AID-IJC

journal_volume

pub_type

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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.