Cationized Bowman-Birk Protease Inhibitor as a Targeted Cancer Chemopreventive Agent

The conjugate of the Bowman-Birk inhibitor (BBI) with poly(D-lysine) (PDL-ss-BBI) has been suggested as a lung-targeted anti-carcinogenic agent. The authors demonstrate that PDL-ss-BBI, given i.p., reduces the tumor number in the lungs of 3-methylcholanthrene treated mice (61-71% compared to control group) in a dose-dependent manner, but is toxic to the treated animals at a high dosage. In order to develop a better lung-targeted anti-carcinogenic agent, spermine-conjugated BBI (spermine-BBI) was synthesized by coupling BBI to spermine through amide bonds using a carbodiimide-mediated reaction. Results from in vitro transformation assays demonstrated that spermine-BBI was at least as effective as BBI in reducing the transformation yield in C3H10T1/2 cells. When injected intravenously into mice [125I]spermine-BBI accumulated to a greater extent in the lungs and the liver compared to BBI. The in vitro cytotoxicity of spermine-BBI in C3H10T1/2 cells was 30-fold less than that of PDL-ss-BBI. These results suggest that spermine-BBI is likely to be an improved cancer chemopreventive agent compared to BBI or PDL-ss-BBI.