title: Inhibition of hepatic metastasis in mice treated with cell-binding domain of human fibronectin and angiogenesis inhibitor TNP-470.
abstract: BACKGROUND
  To prevent tumor metastasis, we administered the cell-binding domain of fibronectin, in combination with the angiogenesis inhibitor TNP-470, to mice with hepatic metastasis. We then assessed the prevention of tumor metastasis resulting from the inhibition of adhesive interactions and the inhibition of angiogenesis.
  
  
  METHODS
  A hepatic metastasis model was created by injecting 1 x 10(3) colon 26/TC-1 cells into the anterior mesenteric vein of CDF1 mice. The cell-binding domain obtained from fibronectin included the Arg-Gly-Asp (RGD) sequence. A fibronectin-binding domain (FND)-treated group, an FND plus TNP-470 group, and a control group were established. The animals were killed 4 weeks after the injections of the treatment agents had been completed and the number of metastatic liver nodules was counted. In a simultaneous experiment with the same design, the mice were not killed at 4 weeks, and their survival was observed.
  
  
  RESULTS
  The mean number of nodules in the FND plus TNP-470 group was significantly lower than that in the control group (P = 0.019337). The inhibition rate was 51% in the FND group, 60% in the FND 10 micrograms plus TNP-470 10 mg/kg group, and 64% in the FND 10 micrograms plus TNP-470 100 mg/kg group compared with the control group. Mice from the FND group that were not killed died after 6-8 weeks, but mice from the FND plus TNP-470 group died after 8-12 weeks.
  
  
  CONCLUSIONS
  The cell-binding domain of fibronectin may, potentially, be an effective form of antiadhesive therapy that competes with native adhesion molecules and blocks adhesion during the metastatic process. When the cell-binding domain of fibronectin is combined with TNP-470 to inhibit angiogenesis, more effective inhibition of metastatic tumor growth and prolongation of survival can be achieved than after treatment with the cell-binding domain alone.
authors.affiliation: Department of Surgery II, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. nobosaito@surg2.twmu.ac.jp
authors.forename: N
authors.initials: N
authors.lastname: Saito
authors.forename: M
authors.initials: M
authors.lastname: Mitsuhashi
authors.forename: T
authors.initials: T
authors.lastname: Hayashi
authors.forename: C
authors.initials: C
authors.lastname: Narumo
authors.forename: H
authors.initials: H
authors.lastname: Nagata
authors.forename: K
authors.initials: K
authors.lastname: Soyama
authors.forename: S
authors.initials: S
authors.lastname: Kameoka
authors.forename: S
authors.initials: S
authors.lastname: Harumiya
authors.forename: D
authors.initials: D
authors.lastname: Fujimoto
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D015179:Colorectal Neoplasms; D003510:Cyclohexanes; D004195:Disease Models, Animal; D005353:Fibronectins / Q000737:chemistry*; D008113:Liver Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D008297:Male; D051379:Mice; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D009842:Oligopeptides / Q000627:therapeutic use*; D012717:Sesquiterpenes / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D005353:Fibronectins; D009842:Oligopeptides; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol