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

J Interferon Cytokine Res. 1995 Feb;15(2):161-9. doi: 10.1089/jir.1995.15.161.

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.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Adhesion*
  • Cell Death
  • Fibrosarcoma / secondary
  • Humans
  • Lung Neoplasms / secondary
  • Lymphatic Metastasis
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / secondary
  • Mice
  • Molecular Sequence Data
  • Mutagenesis, Insertional
  • Neoplasm Metastasis*
  • Oligopeptides / genetics
  • Oligopeptides / physiology*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / physiology*
  • Skin Neoplasms / secondary
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / physiology*

Substances

  • F 4168
  • Oligopeptides
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor-alpha
  • arginyl-glycyl-aspartic acid