title: Cationized Bowman-Birk protease inhibitor as a targeted cancer chemopreventive agent.
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.
authors.affiliation: Department of Pharmaceutical Sciences, John Stauffer Pharmaceutical Sciences Center, University of Southern California School of Pharmacy, Los Angeles 90033.
authors.forename: H
authors.initials: H
authors.lastname: Ekrami
authors.forename: A R
authors.initials: AR
authors.lastname: Kennedy
authors.forename: H
authors.initials: H
authors.lastname: Witschi
authors.forename: W C
authors.initials: WC
authors.lastname: Shen
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002850:Chromatography, Gel; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008748:Methylcholanthrene; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D011107:Polylysine / Q000737:chemistry / Q000494:pharmacology; D013096:Spermine / Q000737:chemistry / Q000494:pharmacology; D014018:Tissue Distribution; D014358:Trypsin Inhibitor, Bowman-Birk Soybean / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D016588:Anticarcinogenic Agents; D014358:Trypsin Inhibitor, Bowman-Birk Soybean; D011107:Polylysine; D013096:Spermine; D008748:Methylcholanthrene; D002918:Chymotrypsin