ANTITUMOR AGENTS EFFECTIVE AGAINST PANCREATIC CANCER

描述(由申请人提供)：建议项目的总体目标是发现在治疗胰腺癌方面有用的新药物。将使用两种方法。第一种方法将研究三类天然产物(Dittyostatin-1、拉索内酯和巴采林)的潜在临床应用，我们已经证明所有这些天然产物都具有良好的抗MDR胰腺肿瘤细胞系的活性。将对这些化合物进行作用机理研究以及体内图谱分析。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肿瘤中发挥作用。重点将放在发现细胞周期特异性因子上。化合物将通过筛选一组胰腺肿瘤细胞系的海洋提取物和磷酸核苷细胞印迹试验来鉴定，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。生物测定引导的分级，然后光谱分析将鉴定新的活性代谢物的结构。 在三年期间，我们建议： 评估三个系列海洋衍生化合物在人胰腺细胞系和胰腺癌实验模型中的体外和体内抗肿瘤活性谱，这些化合物是：敌百虫、拉索内酯和巴采林，以及在授权期的1-3年内发现的化合物。 从5种新近发现的对胰腺肿瘤细胞具有细胞毒作用的提取物中分离鉴定其活性化合物，并测定其体内外抗肿瘤活性。 利用一组人胰腺癌细胞系和磷酸核仁素细胞印迹试验筛选海洋提取物，以发现对胰腺癌具有抗肿瘤活性的新化合物。分离并确定活性化合物的结构。 成功完成拟议的研究将有助于确定新的海洋衍生化合物作为制药公司潜在的许可候选者，用于开发有效对抗胰腺癌的抗肿瘤药物。

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.