This project is designed to develop new agents with dual anti-angiogenic and cytotoxic properties for the chemoprevention and treatment of human lung cancers. Our strategy is to simultaneously attack the endothelial cells of the tumor vascular bed and the tumor cells using a series of novel peptide antagonist monomers and dimers with anti-angiogenic and cytotoxic effects. Recently we found that "third generation" bradykinin (BK) antagonists, with DIgl7 replacements and dimerized with a cross linker greater than six carbon chain length at the N-terminus, were selectively cytotoxic to small cell lung cancer cells (SCLC) in vitro. When injected intratumorally or intraperitoneally, these BK dimers reduced the growth of human lung cancer cells in athymic nude mice in vivo. Furthermore, BK antagonists as well as substance P antagonists have been shown to have inhibitory effects on angiogenesis. The proposed studies will combine a synthetic chemistry effort to design compounds with specific combined bradykinin and neurokinin antagonist activities with an in vitro and in vivo biological program designed to assess their efficacy as cytotoxic agents. These Phase I studies will generate valuable information for a lead-type compound as a potential therapeutic agent for human lung cancers and possibly other cancers in future Phase II studies. Proposed commercial applications: There are no good therapies available for the treatment of human small cell lung carcinomas. 28% of all cancer deaths are due to lung cancer. This is the first report of potent in vitro and in vivo selective cytotoxic agents for lung cancers. These agents can easily be developed as potential therapeutics for lung cancers.
Thesaurus Terms:antineoplastic, cytotoxicity, dimer, drug design /synthesis /production, inhibitor /antagonist, lung neoplasm, peptide bradykinin, calcium flux, chemical synthesis, neoplasm /cancer chemotherapy, small cell lung cancer, substance P athymic mouse, cell line, flow cytometry, laboratory ratNational Cancer Institute (NCI)
