Inhibition of hepatic metastasis in mice treated with cell-binding domain of human fibronectin and angiogenesis inhibitor TNP-470.
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.
Saito
N
N
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
Mitsuhashi
M
M
Hayashi
T
T
Narumo
C
C
Nagata
H
H
Soyama
K
K
Kameoka
S
S
Harumiya
S
S
Fujimoto
D
D
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
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D005353:Fibronectins; D009842:Oligopeptides; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol