Novel Mutein of Tumor Necrosis Factor α (F4614) with Reduced Hypotensive Effect

@article{Shikama1995NovelMO,
  title={Novel Mutein of Tumor Necrosis Factor $\alpha$ (F4614) with Reduced Hypotensive Effect},
  author={Hiroshi Shikama and Keizo Miyata and Nahoko Sakae and Yachiyo Mitsuishi and Koji Nishimura and Kensei Kuroda and Masanari Kato},
  journal={Journal of Interferon and Cytokine Research},
  year={1995},
  volume={15},
  pages={677-684}
}
To eliminate systemic toxicity, including the hypotension associated with human tumor necrosis factor α (TNF-α), we constructed mutant proteins (muteins) by mean of genetic engineering. A novel mutein, F4614, containing mutations of 5Thr → Gly and 6Pro → Asp, which resulted in the introduction of cell-adhesive Arg-Gly-Asp and 29Arg → Val, had remarkably reduced hypotensive effects and lower lethality. We present evidence that the Arg → Val mutation at position 29 is largely responsible for the… Expand
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References

SHOWING 1-10 OF 35 REFERENCES
A novel Mutein of TNFα Containing the Arg-Gly-Asp Sequence Shows Reduced Toxicity in Intestine
TLDR
The results suggest that the Arg-Gly-Asp sequence introduced into the TNFα molecule abrogates the side effect of this cytokine such as tissue injury or shock, and that F4168 could be useful for systemic therapy. Expand
A YIGSR-containing novel mutein without the detrimental effect of human TNF-α of enhancing experimental pulmonary metastasis
The injection of B16F10 melanoma cells with recombinant human tumor necrosis factor alpha (TNF-α) into the tail vein of C57BL/6 mice resulted in 2- to 25-fold more metastatic foci in the lungs thanExpand
A human tumor necrosis factor (TNF) alpha mutant that binds exclusively to the p55 TNF receptor produces toxicity in the baboon
TLDR
It is concluded that selective p55 TNF receptor activation is associated with early hemodynamic changes and the autocrine release of endogenous TNF alpha, but the role of the p75 T NF receptor in systemic TNF toxicity requires further study. Expand
Identity of tumour necrosis factor and the macrophage-secreted factor cachectin
TLDR
It is suggested that the ‘cachectin’ and ‘TNF’ activities of murine macrophage conditioned medium are attributable to a single protein, which modulates the metabolic activities of normal as well as neoplastic cells through interaction with specific high-affinity receptors. Expand
NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide.
  • R. Kilbourn, S. Gross, +4 authors R. Lodato
  • Chemistry, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 1990
TLDR
It is suggested that excessive nitric oxide production mediates the hypotensive effect of TNF, a potent vasodilator initially characterized as endothelium-derived relaxing factor. Expand
Phase I study of recombinant tumor necrosis factor in cancer patients.
TLDR
RTNF was well tolerated clinically in this dose range, and there was evidence of antitumor effect, and the clearance of rTNF in the serum was described by a monoexponential equation with a half-life calculated to be 14-18 min. Expand
Shock and tissue injury induced by recombinant human cachectin.
TLDR
It appears that a single protein mediator (cachectin) is capable of inducing many of the deleterious effects of endotoxin. Expand
Endothelial cell production of nitrogen oxides in response to interferon gamma in combination with tumor necrosis factor, interleukin-1, or endotoxin.
TLDR
It is suggested that endothelial cell-derived nitric oxide plays a role in the development of hypotension in patients treated with tumor necrosis factor or interleukins and that administration of substrate analogues such as L-NMMA may favorably alter the toxicity associated with these immunomodulators and result in a higher maximum tolerated dose, with subsequent improvement in the antitumor activity. Expand
An endotoxin-induced serum factor that causes necrosis of tumors.
TLDR
It is proposed that TNF mediates endotoxin-induced tumor necrosis, and that it may be responsible for the suppression of transformed cells by activated macrophages. Expand
Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro.
TLDR
The observations indicate that the effects of rTNF-alpha on cell growth are not limited to tumor cells, but rather that this protein may have a broad spectrum of activities in vivo. Expand
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