Workshop report from the Division of Cancer Etiology, National Cancer Institute, National Institutes of Health. Protease inhibitors as cancer chemopreventive agents.

This workshop was organized to discuss the current state of research on anticarcinogenic protease inhibitors with regard to their potential use as human cancer chemopreventive agents. Previous studies have indicated that protease inhibitors can be powerful anticarcinogenic agents for animals and cells in culture and that human populations known to have high concentrations of protease inhibitors in the diet have low overall cancer mortality rates. In the workshop discussions, emphasis was placed on certain dietary protease inhibitors, such as the soybean-derived Bowman-Birk inhibitor and chymotrypsin inhibitor 1 from potatoes and some of the highly purified protease inhibitors of microbial origin provided by the Japan Society for the Promotion of Science, which have already been shown to contain anticarcinogenic activity in laboratory studies. Potential adverse side effects of dietary protease inhibitors were also considered, specifically, their possible effects on the pancreas and in causing decreased growth rates in young organisms. It was pointed out that the pancreata of a few species, notably rats and chicks, are extraordinarily sensitive to dietary protease inhibitors. Rats fed diets containing high concentrations of soybean-derived protease inhibitors (raw soy flour) had enlarged pancreata; increased pancreatic growth is thought to accelerate cancer development in the pancreas. The effect of raw soy flour on the growth of the rat pancreas has not been shown to occur in most other species tested (examples include hamsters, mice, dogs, pigs, and monkeys) and is not expected to occur in humans. There is no evidence that dietary protease inhibitors have adverse effects on the human pancreas. In fact, it has been observed that human populations with high levels of dietary protease inhibitors have decreased rates of pancreatic cancer. Dietary concentrations of protease inhibitors which have been shown to be anticarcinogenic have not produced decreased growth rates in animals or any type of pancreatic pathology. In general, there was a high level of enthusiasm at the workshop for the further development of protease inhibitors as chemopreventive agents. Recommendations for future research include: (a) research and development of sources of protease inhibitors; (b) analysis of human foods for protease inhibitor content; (c) evaluation of cancer incidence data in relation to protease inhibitor content and characteristics in the diet of human populations; (d) animal studies on the efficacy of protease inhibitors in cancer prevention; and (e) studies on the mechanism of action of anticarcinogenic protease inhibitors.