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Antisense oligonucleotides against TNFR1 prevent toxicity of TNF/IFNγ treatment in mouse tumor models

(2014) INTERNATIONAL JOURNAL OF CANCER. 135(3). p.742-750
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Abstract
Tumor necrosis factor (TNF) has remarkable antitumor effects, but its systemic therapeutic use is prevented by its lethal inflammatory effects. TNFR1 (P55) is essential for both the antitumor and toxic effects because both of them are absent in P55-deficient mice. In previous work we demonstrated that P55+/- mice are completely resistant to TNF toxicity, while the antitumor effects induced by TNF combined with interferon gamma (IFN gamma) remain fully functional in these mice. Hence, a high dose of TNF/IFN gamma has an excellent therapeutic potential when P55 levels are reduced, because TNF induces tumor regression without systemic toxicity. Here, we provide proof of principle for therapeutic application of this approach by using antisense oligonucleotides (ASOs). Treatment of mice with ASOs targeting P55 resulted in a strong reduction in P55 protein levels in liver, small intestine and blood mononuclear cells. This P55 downregulation was associated with significant protection of mice against acute TNF toxicity as measured by hypothermia, systemic inflammation and lethality. This treatment also protected mice against toxicity of TNF/IFN gamma treatment in several cancer models: B16Bl6, Lewis lung carcinoma and a lung colony model. Our results confirm the therapeutic value of this strategy, which could lead to the development of a safer and more effective TNF/IFN gamma antitumor therapy.
Keywords
TNF/IFN gamma therapy, toxicity, TNFR1, antisense oligonucleotides, NECROSIS-FACTOR-ALPHA, INDUCED LETHAL SHOCK, PHASE-I EVALUATION, RHEUMATOID-ARTHRITIS, ANTITUMOR-ACTIVITY, RECOMBINANT HUMAN, IFN-GAMMA, THERAPY, CANCER, INHIBITION

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Chicago
Van Hauwermeiren, Filip, Roosmarijn Vandenbroucke, Lynda Grine, Leen Puimège, Elien Van Wonterghem, Hong Zhang, and Claude Libert. 2014. “Antisense Oligonucleotides Against TNFR1 Prevent Toxicity of TNF/IFNγ Treatment in Mouse Tumor Models.” International Journal of Cancer 135 (3): 742–750.
APA
Van Hauwermeiren, F., Vandenbroucke, R., Grine, L., Puimège, L., Van Wonterghem, E., Zhang, H., & Libert, C. (2014). Antisense oligonucleotides against TNFR1 prevent toxicity of TNF/IFNγ treatment in mouse tumor models. INTERNATIONAL JOURNAL OF CANCER, 135(3), 742–750.
Vancouver
1.
Van Hauwermeiren F, Vandenbroucke R, Grine L, Puimège L, Van Wonterghem E, Zhang H, et al. Antisense oligonucleotides against TNFR1 prevent toxicity of TNF/IFNγ treatment in mouse tumor models. INTERNATIONAL JOURNAL OF CANCER. 2014;135(3):742–50.
MLA
Van Hauwermeiren, Filip, Roosmarijn Vandenbroucke, Lynda Grine, et al. “Antisense Oligonucleotides Against TNFR1 Prevent Toxicity of TNF/IFNγ Treatment in Mouse Tumor Models.” INTERNATIONAL JOURNAL OF CANCER 135.3 (2014): 742–750. Print.
@article{4420664,
  abstract     = {Tumor necrosis factor (TNF) has remarkable antitumor effects, but its systemic therapeutic use is prevented by its lethal inflammatory effects. TNFR1 (P55) is essential for both the antitumor and toxic effects because both of them are absent in P55-deficient mice. In previous work we demonstrated that P55+/- mice are completely resistant to TNF toxicity, while the antitumor effects induced by TNF combined with interferon gamma (IFN gamma) remain fully functional in these mice. Hence, a high dose of TNF/IFN gamma has an excellent therapeutic potential when P55 levels are reduced, because TNF induces tumor regression without systemic toxicity. Here, we provide proof of principle for therapeutic application of this approach by using antisense oligonucleotides (ASOs). Treatment of mice with ASOs targeting P55 resulted in a strong reduction in P55 protein levels in liver, small intestine and blood mononuclear cells. This P55 downregulation was associated with significant protection of mice against acute TNF toxicity as measured by hypothermia, systemic inflammation and lethality. This treatment also protected mice against toxicity of TNF/IFN gamma treatment in several cancer models: B16Bl6, Lewis lung carcinoma and a lung colony model. Our results confirm the therapeutic value of this strategy, which could lead to the development of a safer and more effective TNF/IFN gamma antitumor therapy.},
  author       = {Van Hauwermeiren, Filip and Vandenbroucke, Roosmarijn and Grine, Lynda and Puim{\`e}ge, Leen and Van Wonterghem, Elien and Zhang, Hong and Libert, Claude},
  issn         = {0020-7136},
  journal      = {INTERNATIONAL JOURNAL OF CANCER},
  keyword      = {TNF/IFN gamma therapy,toxicity,TNFR1,antisense oligonucleotides,NECROSIS-FACTOR-ALPHA,INDUCED LETHAL SHOCK,PHASE-I EVALUATION,RHEUMATOID-ARTHRITIS,ANTITUMOR-ACTIVITY,RECOMBINANT HUMAN,IFN-GAMMA,THERAPY,CANCER,INHIBITION},
  language     = {eng},
  number       = {3},
  pages        = {742--750},
  title        = {Antisense oligonucleotides against TNFR1 prevent toxicity of TNF/IFN\ensuremath{\gamma} treatment in mouse tumor models},
  url          = {http://dx.doi.org/10.1002/ijc.28704},
  volume       = {135},
  year         = {2014},
}

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