Effects of protease inhibitors on levels of proteolytic activity in normal and premalignant cells and tissues.

Abstract

Our studies utilizing different types of protease inhibitors as anticarcinogenic agents in in vivo and in vitro systems have recently been reviewed. These studies suggest that the protease inhibitors which prevent carcinogenesis affect processes in the early stages of carcinogenesis, although they can be effective at long time periods after carcinogen exposure in both in vitro and in vivo systems. While there is strong evidence that these protease inhibitors can affect both the initiation and promotion stages of carcinogenesis, they have no effect on already transformed cells. Our results have suggested that 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 capable of reversing the initiating event, presumably by stopping an ongoing cellular process begun by carcinogen exposure. The major lines of investigation on the mechanism of the protease inhibitor suppression of carcinogenesis relate to the ability of anticarcinogenic protease inhibitors to affect the expression of certain oncogenes, and the levels of certain types of proteolytic activities. The anticarcinogenic protease inhibitors have no observable effects on normal cells, but can reverse carcinogen-induced cellular changes for several different end-points studied. The most direct method of determining the mechanism of action of the anticarcinogenic protease inhibitors is to identify and characterize the proteases with which they interact. In the cells of the in vivo and in vitro systems in which protease inhibitors can prevent carcinogenesis, only a few proteases have been observed to interact with the anticarcinogenic protease inhibitors. Proteases have been identified by both substrate hydrolysis and affinity chromatography.(ABSTRACT TRUNCATED AT 250 WORDS)