ANTITUMOR AGENTS EFFECTIVE AGAINST PANCREATIC CANCER

描述（由申请人提供）：拟议项目的总体目标是发现用于治疗胰腺癌的新型药物。将采用双重方法。第一种方法将研究三种天然产物（dictyostatin-1， lasonolides和batzellines）的潜在临床效用，我们已经证明它们对耐多药胰腺肿瘤细胞系具有出色的活性。将进行这些化合物的作用机制研究以及体内分析。第二种方法将使我们能够发现新的化合物，这些化合物在耐多药耐药肿瘤中具有活性。重点将放在发现细胞周期特异性制剂上。化合物将通过筛选海洋来源的提取物，通过胰腺肿瘤细胞系和磷核蛋白细胞试验来鉴定，该试验检测阻止人类胰腺癌细胞（PANC-1）有丝分裂细胞增殖的化合物。生物测定引导的分馏，随后的光谱分析将确定新的活性代谢物的结构。

DESCRIPTION (provided by applicant): 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.