This grant proposal is the second revision of the competitive renewal of our grant originally submitted in response to RFA No. 87-CA-15. We have proposed experiments to evaluate protease inhibitors as possible human cancer chemopreventive agents, with emphasis on the naturally occurring protease inhibitors present in vegetables such as the soybean derived Bowman-Birk Inhibitor (BBI) and the chick pea inhibitor. In vivo carcinogenesis studies have been proposed to study the efficacy of anticarcinogenic protease inhibitor activity on dimethylhydrazine (DMH) induced colon carcinogenesis in rats. These studies will be performed with soybean-derived BBI and its derivatives (i.e., those compounds we already have available to us which contain known anticarcinogenic activity in vivo or in vitro as determined from our previous studies). We have proposed two different ways to produce anticarcinogenic protease inhibitors with characteristics better than those which exist in those protease inhibitors already available to us; these include: 1) production of synthesized (BBI) gene products, with several modifications to increase the anticarcinogenic activity (the chymotrypsin inhibitory activity); and 2) modifications of BBI and other anticarcinogenic protease inhibitors to result in an increase in uptake from the gastrointestinal tract (into the bloodstream and distribution to other organ sites). As new protease inhibitors become available to us for use, we will first determine their ability to inhibit chymotrypsin and radiation induced transformation in C3H10T1/2 cells. If a compound has these properties, we will determine its ability to: 1) reach the colon in an active form, and 2) be taken up into the bloodstream, and 3) reach organ sites outside the gastrointestinal tract. Long-term animal studies will be performed to determine whether dietary protease inhibitors at anticarcinogenic levels have any effect on the general health of the animals. In these studies, the parameters to be monitored will include: the growth rate of the animals and gross and microscopic pathological changes in the pancreas. The overall aim of this collaborative project is to produce a protease inhibitor containing dietary supplement which can function as a non-toxic chemopreventive agent for human cancer.
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