Anti-tumor effect in an in vivo model by human-derived pancreatic RNase with basic fibroblast growth factor insertional fusion protein through antiangiogenic properties

Cancer Sci. 2006 Dec;97(12):1315-20. doi: 10.1111/j.1349-7006.2006.00336.x. Epub 2006 Oct 9.

Abstract

It is thought that the export of angiogenic fibroblast growth factors (FGF) from tumors may be involved in the onset of tumor angiogenesis. To create a new active targeting drug that inhibits the tumor angiogenic process without toxicities to normal cells, human basic FGF (h-bFGF) was inserted genetically into the Gly89 position of cross-linked RNase1 (the ribonuclease inhibitor protein [RI] binding site of cross-linked human pancreatic RNase) to prevent stereospecific binding to RI. The resultant insertional-fusion protein (CL-RFN89) was active both as h-bFGF and as RNase1. Furthermore, it acquired an additional ability of evading RI through steric blockade of RI binding caused by the fused h-bFGF domain. In the present study, the effect of the resultant protein, CL-RFN89, on the antitumor response though its antiangiogenic properties was investigated in an in vivo model. Continuous systemic treatment with CL-RFN89 significantly inhibited the growth of human A431 squamous cell carcinomas in vivo. Seven days of treatment with CL-RFN89 resulted in a 58.2% inhibition of tumor growth compared with control mice (P < 0.0001). Furthermore, immunohistochemistry using a rat antimouse CD31 antibody showed that treatment with CL-RFN89 reduced tumor vascularization. These findings identify CL-RFN89 as a potent systemic inhibitor of tumor growth as a result of its antiangiogenic properties. This protein appears to be a new systemic antitumor agent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Female
  • Fibroblast Growth Factor 2 / genetics*
  • Fibroblast Growth Factor 2 / metabolism
  • Humans
  • Immunoenzyme Techniques
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / pathology
  • Neovascularization, Pathologic / prevention & control*
  • Plasmids
  • Recombinant Fusion Proteins / therapeutic use*
  • Ribonuclease, Pancreatic / genetics*
  • Ribonuclease, Pancreatic / metabolism
  • Tumor Cells, Cultured

Substances

  • Angiogenesis Inhibitors
  • CL-RFN89 fusion protein
  • Recombinant Fusion Proteins
  • Fibroblast Growth Factor 2
  • Ribonuclease, Pancreatic