title: Anti-tumor effect in an in vivo model by human-derived pancreatic RNase with basic fibroblast growth factor insertional fusion protein through antiangiogenic properties.
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.
authors.affiliation: Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yagi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ueda
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Jinno
authors.forename: Koichi
authors.initials: K
authors.lastname: Aiura
authors.forename: Shuji
authors.initials: S
authors.lastname: Mikami
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tada
authors.forename: Masaharu
authors.initials: M
authors.lastname: Seno
authors.forename: Hidenori
authors.initials: H
authors.lastname: Yamada
authors.forename: Masaki
authors.initials: M
authors.lastname: Kitajima
mesh_terms: 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
chemical_list: D020533:Angiogenesis Inhibitors; C505570:CL-RFN89 fusion protein; D011993:Recombinant Fusion Proteins; D016222:Fibroblast Growth Factor 2; D012259:Ribonuclease, Pancreatic