Related Experiment Videos
Inhibition of and sensitization to the lethal effects of tumor necrosis factor
P Brouckaert1, C Libert, A Cauwels
1Molecular Pathophysiology and Experimental Therapy Unit, Ghent University, Belgium.
Abstract:
The extension of the positive results obtained with tumor necrosis factor (TNF) in the locoregional treatment of cancer to systemic treatments requires the selective inhibition of its shock-inducing properties. In this paper, recent data regarding the mechanisms by which infections and tumors render mice extremely sensitive to the lethal effects of TNF as well as regarding the inhibition of the dose-limiting toxicities, hypotension and hepatotoxicity, are summarized. An interleukin-12 (IL-12) driven induction of interferon-gamma (IFN-gamma), probably in synergism with endogenous TNF, was found to mediate infection-induced sensitization. The sensitization induced by tumors develops independent of the IL-12/IFN-gamma axis but ultimately leads to a common step, which can be inhibited by alpha-CD11a and is specific for sensitization. Hypotension can be inhibited by methylene blue (MB), an inhibitor of the nitric oxide (NO)-induced activation of the cytosolic guanylate cyclase, without the indispensable protective properties of NO being affected. Finally, two acute phase proteins, alpha 1-acid-glycoprotein (AGP) and alpha 1-antitrypsin (AT), were able to protect against the TNF-induced liver failure. None of these three inhibitors seems to affect the antitumor effects of TNF.
Insights
Researchers identified mechanisms to safely use tumor necrosis factor (TNF) systemically for cancer treatment by inhibiting its toxic shock effects. Inhibitors targeting infection- or tumor-induced sensitivity, hypotension, and liver failure were explored without compromising anti-cancer activity.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Tumor necrosis factor (TNF) shows promise in locoregional cancer treatment.
- Systemic application of TNF is limited by dose-limiting toxicities like hypotension and hepatotoxicity.
- Understanding sensitization mechanisms to TNF's lethal effects is crucial for safe systemic therapy.
Purpose of the Study:
- To summarize recent data on mechanisms of TNF hypersensitivity induced by infections and tumors.
- To review strategies for inhibiting TNF-induced hypotension and hepatotoxicity.
- To assess if identified inhibitors affect TNF's anti-tumor efficacy.
Main Methods:
- Review of recent data on infection- and tumor-induced TNF sensitization mechanisms in mice.
- Investigation of inhibitors for hypotension (methylene blue) and hepatotoxicity (alpha 1-acid-glycoprotein, alpha 1-antitrypsin).
- Evaluation of alpha-CD11a for inhibiting a common sensitization step.
Main Results:
- Infection-induced TNF hypersensitivity mediated by interleukin-12 (IL-12) and interferon-gamma (IFN-gamma).
- Tumor-induced sensitization involves a pathway independent of IL-12/IFN-gamma but inhibitable by alpha-CD11a.
- Methylene blue inhibited hypotension; AGP and AT protected against liver failure, without affecting anti-tumor effects.
Conclusions:
- Selective inhibition of TNF's toxic properties is achievable, enabling potential systemic cancer treatment.
- Distinct mechanisms underlie infection- and tumor-induced TNF hypersensitivity.
- Identified inhibitors (methylene blue, AGP, AT) mitigate TNF toxicity without compromising anti-tumor activity.