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Fas receptor-mediated apoptosis: a clinical application?
Tineke Timmer1, Elisabeth G E de Vries, Steven de Jong
1Division of Medical Oncology, University Hospital Groningen, The Netherlands. t.timmer@int.azg.nl
Abstract:
Fas is a membrane protein belonging to the death receptor family. Cross-linking of Fas by its ligand, FasL, or agonistic anti-Fas antibodies, induces apoptosis of cells expressing Fas on the membrane by triggering a cascade of caspases. Since many different tumours express Fas on their membrane, targeting Fas-mediated apoptosis by anti-Fas antibodies may be a promising anticancer therapy. Unfortunately, not all Fas-expressing cells are sensitive to Fas-mediated apoptosis. This has resulted in the discovery of many different inhibition mechanisms of Fas-mediated apoptosis. In addition, mutations in the Fas or p53 gene can also influence the sensitivity for Fas-mediated apoptosis. However, the role of wild-type p53 in Fas expression is still controversial. Because several different cytotoxic drugs are able to induce Fas membrane expression, combination therapy of anticancer drugs with anti-Fas antibodies or FasL is conceivable as an anticancer strategy. The efficiency of the induction of Fas-mediated apoptosis by anti-Fas antibodies, FasL-expressing cells or recombinant FasL (rFasL) in tumours has been demonstrated in vivo in solid tumours implanted in mice. Unfortunately, systemic treatment with anti-Fas antibodies or rFasL causes severe damage to the liver, so most preclinical studies are now focusing on circumvention of this problem by local administration of FasL, or on the use of inducible FasL-expressing vectors as gene therapy.
Insights
Targeting Fas-mediated apoptosis with anti-Fas antibodies shows promise for cancer therapy. However, resistance and liver toxicity necessitate exploring combination therapies and localized Fas ligand delivery strategies.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Fas (also known as CD95 or APO-1) is a death receptor crucial for initiating apoptosis.
- Fas-mediated apoptosis can be triggered by Fas ligand (FasL) or agonistic anti-Fas antibodies, leading to caspase activation.
- Many tumors express Fas, making it a potential therapeutic target for cancer treatment.
Purpose of the Study:
- To explore the potential of targeting Fas-mediated apoptosis as an anticancer therapy.
- To investigate mechanisms of resistance to Fas-mediated apoptosis.
- To evaluate combination therapy strategies involving anti-Fas antibodies or FasL with cytotoxic drugs.
Main Methods:
- In vivo studies using solid tumors implanted in mice.
- Administration of anti-Fas antibodies, FasL-expressing cells, or recombinant FasL (rFasL).
- Investigation of tumor sensitivity to Fas-mediated apoptosis.
Main Results:
- Fas-mediated apoptosis can be induced by anti-Fas antibodies, FasL-expressing cells, or rFasL in tumors.
- Resistance to Fas-mediated apoptosis occurs due to various inhibition mechanisms and potential mutations in Fas or p53.
- Systemic administration of anti-Fas antibodies or rFasL resulted in significant liver toxicity.
Conclusions:
- Targeting Fas-mediated apoptosis is a promising anticancer strategy, but clinical application is limited by resistance and toxicity.
- Combination therapy with cytotoxic drugs may enhance efficacy.
- Local administration of FasL or gene therapy using inducible FasL vectors are potential strategies to overcome systemic toxicity and improve therapeutic outcomes.