The projects proposed in this grant cover several of the research areas listed in 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), the chick pea inhibitor, and the potato chymotrypsin inhibitor). In vivo carcinogenesis studies have been proposed to study the efficacy of anticarcinogenic protease inhibitor activity on methylbenzylnitrosamine (MBNA)-induced esophageal carcinogenesis in rats (or 7,12-dimethylbenz(a) anthracene (DMBA) induced oral carcinogenesis in hamsters) and chemically induced lung tumor development (with and without promotion by butylated hydroxytoluene) in mice, hamsters and rats. These studies will be performed with soybean-derived BBI and its derivatives or the potato chymotrypsin inhibitor (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 eliminate potentially toxic side effects (due to trypsin 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 C3H10T 1/2 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 1) any possible effects on the immune system; 2) the growth rate of the animals; and 3) 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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