ANTITUMOR AGENTS EFFECTIVE AGAINST PANCREATIC CANCER

有效对抗胰腺癌的抗肿瘤药物

• 批准号: 6572826
• 负责人: AMY Elizabeth WRIGHT
• 金额: $ 32.93万
• 依托单位: HARBOR BRANCH OCEANOGRAPHIC INST, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6572826
• 关键词: affinity chromatography; animal extract; antineoplastics; aquatic organism; athymic mouse; bioassay; biological products; biotechnology; cell line; cell surface receptors; confocal scanning microscopy; cytotoxicity; drug discovery /isolation; drug screening /evaluation; flow cytometry; gel electrophoresis; high performance liquid chromatography; liquid chromatography mass spectrometry; microarray technology; multidrug resistance; neoplasm /cancer chemotherapy; nuclear magnetic resonance spectroscopy; pancreas neoplasms; pharmacokinetics; thin layer chromatography

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.

描述（由申请人提供）：拟议项目的总体目标是发现可用于治疗胰腺癌的新型药物。将采用双重办法。第一种方法将研究三类天然产物（dictyostatin-1、lasonolides和batzellines）的潜在临床用途，我们已经证明所有这些天然产物对MDR抗性胰腺肿瘤细胞系具有优异的活性。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MDR抗性肿瘤中具有活性。重点将放在细胞周期特异性药物的发现上。将通过一组胰腺肿瘤细胞系和检测阻断人胰腺癌细胞（PANC-1）的有丝分裂细胞增殖的化合物的膦酰基核蛋白细胞色素分析筛选海洋来源的提取物来鉴定化合物。生物测定引导的分级分离，然后进行光谱分析，将确定新的活性代谢物的结构。 在这三年期间，我们建议： 评估三个系列的海洋衍生化合物在人类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：dictyostatins; lasonolides和batzellines以及在资助期的第1-3年发现的化合物。 分离和确定最近被鉴定为对胰腺肿瘤细胞具有细胞毒性的五种提取物的活性化合物的结构，并确定其体外和体内抗肿瘤活性。 使用一组人胰腺癌细胞系和膦酰基核菌素细胞色素分析筛选海洋提取物，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开发有效治疗胰腺癌的抗肿瘤药物的潜在许可候选者。