Related Experiment Videos
Cationized Bowman-Birk protease inhibitor as a targeted cancer chemopreventive agent
H Ekrami1, A R Kennedy, H Witschi
1Department of Pharmaceutical Sciences, John Stauffer Pharmaceutical Sciences Center, University of Southern California School of Pharmacy, Los Angeles 90033.
Abstract:
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.
Insights
Spermine-conjugated Bowman-Birk inhibitor (BBI) shows promise as a lung-targeted cancer chemopreventive agent. Spermine-BBI is effective and less toxic than previous conjugates, suggesting improved therapeutic potential.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- The Bowman-Birk inhibitor (BBI) conjugate with poly(D-lysine) (PDL-ss-BBI) was investigated as a lung-targeted anti-carcinogenic agent.
- PDL-ss-BBI demonstrated dose-dependent reduction in lung tumors in mice but exhibited toxicity at higher doses.
Purpose of the Study:
- To develop an improved lung-targeted anti-carcinogenic agent.
- To synthesize and evaluate spermine-conjugated BBI (spermine-BBI) as a potential cancer chemopreventive agent.
Main Methods:
- Spermine-BBI was synthesized by coupling BBI to spermine via amide bonds using carbodiimide chemistry.
- In vitro transformation assays using C3H10T1/2 cells were performed to assess efficacy.
- Biodistribution studies using [125I]spermine-BBI were conducted in mice.
- In vitro cytotoxicity assays were performed on C3H10T1/2 cells.
Main Results:
- Spermine-BBI exhibited comparable efficacy to BBI in reducing transformation yield in vitro.
- Intravenous injection of [125I]spermine-BBI resulted in greater accumulation in the lungs and liver compared to BBI.
- Spermine-BBI demonstrated 30-fold lower in vitro cytotoxicity than PDL-ss-BBI in C3H10T1/2 cells.
Conclusions:
- Spermine-BBI represents a potentially improved lung-targeted cancer chemopreventive agent.
- The reduced toxicity and favorable biodistribution profile suggest spermine-BBI could be a viable alternative to BBI and PDL-ss-BBI.