Effect of a matrix metalloproteinase inhibitor (ONO-4817) on lung metastasis of murine renal cell carcinoma.
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.
Muraishi
Y
Y
Department of Pathogenic Biochemistry, Institute of Natural Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Sugitani, Japan.
Mitani
N
N
Fuse
H
H
Saiki
I
I
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000517:prevention & control* / Q000556:secondary*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010647:Phenyl Ethers / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*
D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; C414368:N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide; D010647:Phenyl Ethers; D011480:Protease Inhibitors; D020778:Matrix Metalloproteinase 2