Protease inhibitors (PIs), particularly the soybean-derived Bowman-Birk inhibitor, have proved to be powerful blockers of carcinogenesis in many in vitro and animal model systems. However, so far an ability of PIs to suppress gastric carcinogenesis has not been demonstrated, because of the anticipated 'hostile' acidic gastric environment for the PI to exert its action. We therefore examined the ability of a purified PI from the Indian legume the field bean (FBPI), when administered by gavage, to subdue benzopyrene (BP)-induced neoplasia of the forestomach of mice. Forestomach tumors were produced in female Swiss albino mice by oral administration of BP at a dose of 1 mg twice weekly for 4 weeks. Groups of mice were treated per os with an aqueous solution of FBPI for 3 months or more at a dose of 20 mg/kg once daily, six times a week, either from the initiation of carcinogenesis or after completion of the carcinogen treatment. Another group was treated likewise with autoclaved inactive FBPI. Mice of both the FBPI-treated groups showed statistically significant (P < 0.001) reductions in the multiplicity of gastric tumors, with the tumor incidence being unaffected. However, the suppression of tumor multiplicity was appreciably (P < 0.01) more in the group that received FBPI treatment concomitantly with the carcinogen. The mice that were treated with heat-inactivated FBPI showed similar tumor multiplicity to the BP-treated group, indicating that the oncopreventive activity of FBPI is related to its protease inhibitory capacity. These observations point to the potential of PIs as effective chemoprotectors against gastric cancer in animals and, possibly, in humans as well.

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Protease inhibitor preparations (PIP) with antitryptic and antichymotryptic activities, isolated from field bean legume as well as doxorubicin and cyclophosphamide could effectively suppress the growth of Yoshida sarcoma ascites tumor cells transplanted in adult rats and prevent their death. As against this, methotrexate and heat-inactivated PIP were ineffective in such rats at varied doses of treatment tried. The percent survival of animals appeared to be related to the purity, treatment mode and the dose of PIP used. Zymographic analysis of the trypsin activated sarcoma cell homogenate revealed the presence of six protease bands in the molecular weight range of 51kD to 206kD. Prolonged interactions of such zymograms with protease inhibitors such as 20mM EDTA or 5mM diisopropyl flurophosphate (DIFP) or 400 micrograms/ml of PIP in reaction buffer indicated that these are not metalloproteases but serine proteases whose activities are inhibited by PIP and DIFP. Since proteases are involved in cell growth regulation and cell transformation, we hypothesize a positive relationship between the field bean protease inhibitor's blocking action on tumor cell proteases and its tumor suppressing activity.

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