Effect of a matrix metalloproteinase inhibitor (ONO-4817) on lung metastasis of murine renal cell carcinoma.

Abstract

We examined the anti-metastatic effect of a newly developed inhibitor of synthetic matrix metalloproteinase (MMP), ONO-4817, on experimental pulmonary metastasis of murine renal cell carcinoma (Renca) cells and on tumor cell invasion, through reconstituted basement membrane (Matrigel) in vitro using the same cells. Oral administration of ONO-4817 (50-200 mg/kg/day) to Renca-bearing mice resulted in a dose-dependent inhibition of lung metastasis without a loss of body weight. ONO-4817 at the high dose of 200 mg/kg showed a tendency to prolong the survival of the mice. We also found that oral administration of ONO-4817 significantly inhibited the angiogenic response (number of vessels oriented towards the tumor mass) and the growth of tumors inoculated i.d. in syngeneic mice. In addition, ONO-4817, at non-cytotoxic concentrations of less than 10 microM, caused a marked inhibition of the invasion of Renca cells as compared to the vehicle control. Gelatin zymography revealed that ONO-4817 inhibited the enzymatic activity of MMP-2 produced by Renca cells in a concentration-dependent manner. In conclusion, ONO-4817 effectively inhibited lung metastasis of Renca cells through its anti-invasive and anti-angiogenic properties. These results suggest that use of the MMP inhibitor (MMPI) ONO-481 7 may provide a therapeutic basis for preventing lung recurrence and metastasis of renal cell carcinoma.

• Authors: Y Muraishi, N Mitani, H Fuse, I Saiki
• Journal: Anticancer research (Anticancer Res) 2001 Nov-Dec Vol. 21 Issue 6A Pg. 3845-52 ISSN: 0250-7005 [Print] Greece
• PMID: 11911256 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Matrix Metalloproteinase Inhibitors
• N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide
• Phenyl Ethers
• Protease Inhibitors
• Matrix Metalloproteinase 2

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Renal Cell (drug therapy, prevention & control, secondary)
• Cell Adhesion (drug effects)
• Cell Division (drug effects)
• Cell Movement (drug effects)
• Female
• Kidney Neoplasms (drug therapy, pathology)
• Lung Neoplasms (prevention & control, secondary)
• Matrix Metalloproteinase 2 (biosynthesis, metabolism)
• Matrix Metalloproteinase Inhibitors
• Mice
• Mice, Inbred BALB C
• Neovascularization, Pathologic (prevention & control)
• Phenyl Ethers (pharmacology)
• Protease Inhibitors (pharmacology)