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Overcoming the metastasis-enhancing potential of human tumor necrosis factor alpha by introducing the cell-adhesive Arg-Gly-Asp sequence.

Abstract
A mutein, F4168, of human tumor necrosis factor alpha (hTNF-alpha) containing the cell-adhesive Arg-Gly-Asp (RGD) sequence near the N terminus was constructed. In contrast to hTNF-alpha, the mutein had binding activity to B16F10/L5 melanoma cells similar to that of fibronectin or laminin, indicating that the adhesive nature of the RGD sequence is conferred upon hTNF-alpha. Introduction of the RGD sequence did not alter the antitumor potential of hTNF-alpha. Simultaneous injection of F4168 and B16F10/L5 melanoma cells into mice did not enhance metastasis formation in lungs, whereas hTNF-alpha significantly promoted it. Enhancement of spontaneous lymph node metastasis of B16F10/L5 cells was also evident in TNF-alpha- but not in F4168-treated mice. In the spontaneous lymph node metastasis model of MethA fibrosarcoma, F4168 injection inhibited metastasis formation more effectively than hTNF-alpha. B16F10/L5 melanoma cells treated with hTNF-alpha enhanced not only their binding activity to laminin but also their invasive potential into Matrigel, whereas F4168 showed no such enhancement. These results suggest that F4168 is a low-toxicity mutein of hTNF-alpha.
AuthorsK Miyata, Y Mitsuishi, H Shikama, K Kuroda, K Nishimura, N Sakae, M Kato
JournalJournal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research (J Interferon Cytokine Res) Vol. 15 Issue 2 Pg. 161-9 (Feb 1995) ISSN: 1079-9907 [Print] United States
PMID8590320 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • F 4168
  • Oligopeptides
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor-alpha
  • arginyl-glycyl-aspartic acid
Topics
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Adhesion
  • Cell Death
  • Fibrosarcoma (secondary)
  • Humans
  • Lung Neoplasms (secondary)
  • Lymphatic Metastasis
  • Melanoma, Experimental (pathology, secondary)
  • Mice
  • Molecular Sequence Data
  • Mutagenesis, Insertional
  • Neoplasm Metastasis
  • Oligopeptides (genetics, physiology)
  • Recombinant Fusion Proteins (genetics, physiology)
  • Skin Neoplasms (secondary)
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha (genetics, immunology, metabolism, physiology)

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