Anti-invasive activity of synthetic serine protease inhibitors and its combined effect with a matrix metalloproteinase inhibitor.

Abstract

Tumor invasion into the extracellular matrix (ECM) and basement membrane (BM) is a crucial step of tumor metastasis. In order to investigate the possible therapeutic procedure for the tumor invasion, we investigated the anti-invasive activities of several synthetic serine protease inhibitors. FOY-305, a serine protease inhibitor, showed no cytotoxic activity against human HT-1080 fibrosarcoma cells at concentrations ranging from 0.1 to 100 micrograms/ml, while its analogs ONO-3403 and FO-349 showed slight cytotoxic activities at the concentration of 100 micrograms/ml. These compounds inhibited the activity of urokinase-type plasminogen activator (u-PA) which is one of serine proteases and considered to be associated with tumor invasion and metastasis in fibrin zymography. FOY-305 more potently inhibited the invasion of HT-1080 cells into the reconstituted BM Matrigel, as well inhibited u-PA activity, compared with ONO-3403 and FO-349. These results suggest that the anti-invasive activity of these compounds is consistent with their anti-fibrinolytic activities. In addition, the combined treatment of FOY-305 with FC-336 processing anti-invasive and anti-MMP properties resulted in marked enhancement of anti-invasive activity. In conclusion, FOY-305 inhibited the invasion of tumor cells through interference with the u-PA activity of tumor cells, and this inhibitory activity was augmented by the combination with a MMP inhibitor.

• Authors: T Ikeda, K Murakami, Y Hayakawa, H Fujii, M Ohkoshi, I Saiki
• Journal: Anticancer research (Anticancer Res) 1998 Nov-Dec Vol. 18 Issue 6A Pg. 4259-65 ISSN: 0250-7005 [Print] Greece
• PMID: 9891476 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amidines
• Antineoplastic Agents
• Benzamidines
• Benzoates
• Esters
• Guanidines
• ONO-FO 349-01
• Serine Proteinase Inhibitors
• ethyl N-allyl-N-(2-methyl-3-(4-(4-amidinophenoxycarbonyl)phenyl)propenoyl)aminoacetate methanesulfonate
• camostat
• Allylglycine
• Gabexate
• Urokinase-Type Plasminogen Activator

Topics

• Allylglycine (analogs & derivatives, toxicity)
• Amidines (toxicity)
• Antineoplastic Agents (toxicity)
• Benzamidines (toxicity)
• Benzoates (toxicity)
• Cell Survival (drug effects)
• Esters
• Fibrosarcoma (pathology)
• Gabexate (analogs & derivatives)
• Guanidines (toxicity)
• Humans
• Kinetics
• Neoplasm Invasiveness (prevention & control)
• Serine Proteinase Inhibitors (toxicity)
• Structure-Activity Relationship
• Tumor Cells, Cultured
• Urokinase-Type Plasminogen Activator (antagonists & inhibitors)