Potential mechanisms of antitumorigenesis by protease inhibitors.

The mechanisms by which protease inhibitors suppress carcinogenesis are unknown. From our studies, we believe the first event in carcinogenesis is a high frequency epigenetic event and that a later event (presumably genetic) leads to the malignant state. Protease inhibitors appear to be capable of reversing the "initiating" event in carcinogenesis, even at long times after carcinogen exposure. Protease inhibitors are thought to stop an ongoing process begun by carcinogen exposure. Effects of protease inhibitors on the following phenomena are thought to be related to their anticarcinogenic activity: 1) ability to effect the expression of certain oncogenes, and 2) ability to return carcinogen-increased levels of certain proteolytic activities (e.g., Boc-val-pro-arg-MCA hydrolyzing activity) to normal levels. Other effects of anticarcinogenic protease inhibitors have also been observed; for example, we have reported that they can bring carcinogen-induced, elevated levels of gene amplification to nearly normal levels. The mechanism(s) by which protease inhibitors suppress carcinogenesis will not be determined with certainty until the mechanisms involved in cancer induction are known.