Therapeutic efficacy of once-daily oral administration of a Kunitz-type protease inhibitor, bikunin, in a mouse model and in human cancer.

BACKGROUND: Bikunin, a Kunitz-type protease inhibitor, specifically inhibits tumor invasion and metastasis. METHODS: The authors initially evaluated the therapeutic efficacy of once-daily oral administration of different doses of bikunin against human ovarian carcinoma HRA cells growing in the peritonea of nude mice. For the in vivo studies, female 7-week-old nude mice were randomized to 1 of 4 groups: bikunin-treated groups (n = 9 in each group) received 3, 10, or 30 microg/g body weight per day bikunin for 7 days via gastrointestinal gavage, and a control group (n = 9) received the vehicle solution (phosphate-buffered saline) via gastrointestinal gavage. On Day 9, the abdominal cavity was examined by two observers who were blinded to treatment. RESULTS: After oral administration, intact bikunin was detectable in mouse serum specimens at 3 and 6 hours. This was followed by a decline at 12 hours. The mice given bikunin at the highest dose level had a 40% decrease in tumor load. The highest uptake in the tumor was obtained with [125I]bikunin 12 hours postadministration. No effect on either food intake or body weight was observed in the treated versus sham groups. The current study was the first to report the potent activity of once-daily oral administration of bikunin against ovarian carcinoma. Next, the authors performed a Phase I trial to determine the maximum-tolerated dose (MTD) and safety of a once-daily oral administration schedule. The indication was locally advanced uterine cervical carcinoma after definitive treatment. An escalating dose (3, 10, and 30 mg/kg per day) of bikunin was administered orally to nine patients for 7 days. There were no dose-limiting toxicities and the MTD of the bikunin schedule was not defined. The authors also obtained preliminary data on its effect on urokinase-type plasminogen activator expression at the highest dose level. CONCLUSIONS: Once-daily oral administration of bikunin was found to be safe in humans and exhibited signs of biologic activity.

Possible adverse effects of soybean anticarcinogens.

For soybeans to serve as a good source of protein for feeding animals as well as humans, a certain amount of heat treatment or some other form of processing must be applied. This is because there are present in soybeans certain heat-labile factors that exert an adverse effect on the nutritional value of the protein. The so-called protease inhibitors have received the most attention in this regard and have been shown to exert their antinutritional effect in the short term by causing pancreatic hypertrophy and hyperplasia in the rat, the underlying cause for an inhibition of growth in these animals. The prolonged feeding of raw soy flour or an enriched trypsin inhibitor fraction from soybeans to rats results in the development of hyperplastic and neoplastic nodules of the pancreas, including carcinomas. It should be emphasized that all of these adverse effects are seen when protease inhibitors are present in relatively high concentrations in the diet and may be completely unrelated to the anticarcinogenic effects seen at low concentrations of the Bowman-Birk inhibitor. Brief mention is also made of any possible adverse effects that may result from the presence of phytic acid and saponins in soybeans.

Pancreatic enlargement is evident in rats fed diets containing raw soybeans (Glycine max) or cowpeas (Vigna unguiculata) for 800 days but not in those fed diets based on kidney beans (Phaseolus vulgaris) or lupinseed (Lupinus angustifolius).

Pancreatic weights and composition were studied with rats fed diets containing raw legume seeds for up to 800 d. Rapid pancreatic enlargement was induced by dietary soybeans (Glycine max) (high Kunitz and Bowman-Birk trypsin inhibitor contents, moderate lectin content) during the initial 150 d. Over the next 200 d the rate of pancreatic growth was similar to that in controls. After 350 d a second period of rapid pancreatic growth occurred. Macroscopic pancreatic nodules were evident in a number of rats fed soybeans for 500 d or more. A similar pattern of pancreatic growth was observed in rats fed dietary cowpeas (Vigna unguiculata) (high Bowman-Birk inhibitor content, low lectin content). Extensive pancreatic growth was also found in young rats fed moderate dietary levels of kidney beans (Phaseolus vulgaris) (low Bowman-Birk inhibitor content, high lectin content). However, the trophic effects diminished with time, and from 100 d onwards, little enlargement was evident. Consumption of a lupinseed (Lupinus angustifolius) diet (low trypsin inhibitor, low lectin content) did not cause pancreatic enlargement. The initial pancreatic growth induced by dietary soybeans seemed to be due to the lectins and trypsin inhibitors, whereas the second period of pancreatic growth was possibly due primarily to the trypsin inhibitors.