Anti-tumor effect in an in vivo model by human-derived pancreatic RNase with basic fibroblast growth factor insertional fusion protein through antiangiogenic properties.
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.
Yagi
Hiroshi
H
Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
Ueda
Masakazu
M
Jinno
Hiromitsu
H
Aiura
Koichi
K
Mikami
Shuji
S
Tada
Hiroko
H
Seno
Masaharu
M
Yamada
Hidenori
H
Kitajima
Masaki
M
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010957:Plasmids; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D012259:Ribonuclease, Pancreatic / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; C505570:CL-RFN89 fusion protein; D011993:Recombinant Fusion Proteins; D016222:Fibroblast Growth Factor 2; D012259:Ribonuclease, Pancreatic