The overall objective of the proposed project is to discover novel agents with utility in the treatment of pancreatic cancer. A two-fold approach will be used. The first approach will investigate the potential clinical utility of three classes of natural products (dictyostatin-1, the lasonolides and the batzellines, all of which we have shown have excellent activity against MDR resistant pancreatic tumor cell lines. Mechanism of action studies as well as in vivo profiling of these compounds will be undertaken. The second approach will allow us to discover new compounds, which are active in MDR resistant tumors. The focus will be on the discovery of cell cycle specific agents. Compounds will be identified by screening marine-derived extracts through a panel of pancreatic tumor cell lines and the phosphonucleolin cytoblot assay which detects compounds which block mitotic cell proliferation of human pancreatic cancer cells (PANC-1). Bioassay-guided fractionation, followed by spectroscopic analysis will identify the structures of the new active metabolites. For the three year period we propose to: Evaluate the in vitro and in vivo spectrum of antitumor activity in human pancreatic cell lines and in experimental models of pancreatic cancer for three series of marine derived compounds: the dictyostatins; the lasonolides and the batzellines as well as for compounds discovered during Years 1-3 of the grant period. Isolate and determine the structures of the active compounds of five extracts recently identified to be cytotoxic towards pancreatic tumor cells and determine their in vitro and in vivo antitumor activities. Screen marine extracts using a panel of human pancreatic cancer cell lines and the phosphonucleolin cytoblot assay in order to discover novel compounds with antitumor activity towards pancreatic cancer. Isolate and determine the structures of the active compounds. Successful completion of the proposed research will serve to identify new marine derived compounds as potential licensing candidates to pharmaceutical companies for development as antitumor agents effective against pancreatic cancer.
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