The major cause of cancer appears to be the environment. Estimates of 80-90% of cancer incidence have been ascribed to environmental factors. Carcinogenesis is a multistep process which can be conceptually subdivided into initiation and promotion areas. Cancer could be prevented by avoiding exposure to initiating carcinogens or by interfering with the biological processes leading to neoplastic transformation. We propose to prevent cancer by modifying the biological response with protease inhibitors. A novel application in the use of protease inhibitors is in feeding diets containing natural protease inhibitors e.g., soybeans. Protease inhibitors (antipain, tosyllysine chloromethyl ketone (TLCK)) have been shown to block error-prone repair of DNA. TLCK, Tosyllysine phenylalanine chloromethyl ketone (TPCK) and leupeptin applied to skin and soybean trypsin inhibitors in the diet have been shown to interfere with promotion by the tumor promoter 12-O-Tetradecanoyl-phorbol-13-Acetate (TPA). Protease inhibitors in the diet have suppressed breast cancer response in Sprague-Dawley rats. The high occurrence of protease inhibitors in plants may be responsible for the low cancer occurrence in vegetarian populations. The Seventh-Day Adventists exhibit low breast and colon cancer--cancers whose occurrence are not related to cigarette smoking. To support this thesis, we will feed protease inhibitors extracted from plant products used in human nutrition, e.g., beans, peanuts, corn and potatoes to animals subjected to carcinogenesis and compare the tumor yield to those fed a diet free of protease inhibitors. The animal systems which will be used are two-stage carcinogenesis in the mouse, breast and bladder cancer in the rat. Two protease inhibitors from the soybean have been purified and extensively studied--the Kunitz inhibitor MW 21.500 and the Bowman-Birk inhibitor MW 21.500 and the Bowman-Birk inhibitor MW 8000. We will study the digestion of these inhibitors by pepsin and absorption of radioactively labeled inhibitors or its digestion products on feeding to animals. The heat stable Bowman-Birk inhibitor has been shown to yield smaller fragments still capable of inhibiting proteases. The occurrence of protease inhibitors in human food materials (cereals, bread, cooked beans, peanuts) will be investigated, in order to identify foods with (Text Truncated - Exceeds Capacity)