Abstract | BACKGROUND: The transmembrane receptor Fas, together with its protein-binding partner ( Fas ligand), is a key regulator of programmed cell death (i.e., apoptosis). Fas and Fas ligand also influence the ability of cytotoxic T lymphocytes and natural killer cells to eliminate tumor cells. However, by inducing apoptosis in activated T cells, the Fas/ Fas ligand system may protect some tumor cells from clearance by the immune system. Anticancer drugs enhance Fas ligand expression on the surface of Fas receptor-expressing leukemia cells, thus suggesting that apoptosis caused by these drugs may be mediated via the Fas/ Fas ligand system. PURPOSE: This study was conducted to further investigate the relationship between the modulation of Fas receptor gene and protein expression by treatment of cells with cytotoxic drugs and the immune clearance of tumor cells. METHODS: RESULTS: Clinically relevant concentrations of cisplatin, doxorubicin, mitomycin C, fluorouracil, or camptothecin enhanced Fas receptor expression on the plasma membrane of HT29 cells. Cisplatin-mediated increases in Fas expression were confirmed in HCT8R, HCT116, and U937 cells. The enhancement of Fas protein expression was associated with an increased sensitivity of cisplatin-treated tumor cells to agonistic anti-Fas antibodies, to soluble Fas ligand, and to allogeneic peripheral blood leukocyte-mediated cytotoxicity. Each of these effects was blocked by co-treatment of the cells with antagonistic anti-Fas antibody. CONCLUSION AND IMPLICATIONS: In addition to their direct cytotoxic effects, chemotherapeutic drugs sensitize tumor cells to Fas-mediated cytotoxicity and Fas-dependent immune clearance. On the basis of these findings, new strategies might be developed to improve the efficacy of these drugs.
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Authors | O Micheau, E Solary, A Hammann, F Martin, M T Dimanche-Boitrel |
Journal | Journal of the National Cancer Institute
(J Natl Cancer Inst)
Vol. 89
Issue 11
Pg. 783-9
(Jun 04 1997)
ISSN: 0027-8874 [Print] United States |
PMID | 9182976
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- FASLG protein, human
- Fas Ligand Protein
- Fasl protein, mouse
- Membrane Glycoproteins
- RNA, Messenger
- fas Receptor
- Cisplatin
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects, physiology)
- Cisplatin
(pharmacology)
- Colonic Neoplasms
(drug therapy)
- Drug Screening Assays, Antitumor
- Fas Ligand Protein
- Flow Cytometry
- HT29 Cells
(drug effects, metabolism)
- Humans
- Membrane Glycoproteins
(drug effects, metabolism, physiology)
- Mice
- RNA, Messenger
(metabolism)
- Tumor Cells, Cultured
- fas Receptor
(drug effects, metabolism, physiology)
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