ANTITUMOR AGENTS EFFECTIVE AGAINST PANCREATIC CANCER

有效对抗胰腺癌的抗肿瘤药物

• 批准号: 7626984
• 负责人: AMY Elizabeth WRIGHT
• 金额: $ 9.18万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7626984
• 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）：拟议项目的总体目的是发现具有治疗胰腺癌治疗的新型药物。将使用两倍的方法。第一种方法将研究三类天然产物的潜在临床实用性（Dictyostatin-1，Lasonolides和Batzellines，我们所显示的所有这些都具有极好的活性，以抵抗MDR耐药性胰腺肿瘤细胞系。动作研究的机制以及这些化合物的体内方法将允许新的景点。细胞周期特异性化合物将通过胰岛细胞系和磷核蛋白细胞细胞生成测定，从而鉴定出有丝分裂细胞的胰岛细胞增殖，从而确定人类胰腺癌细胞的分析，从而鉴定出有丝分裂细胞的肿瘤，从而确定了分析的生物，从而确定了细胞周期的特定化合物。 在三年期间，我们建议： 评估人类胰腺细胞系中抗肿瘤活性的体外和体内谱，以及三个系列海洋衍生化合物的胰腺癌实验模型中：dictyostatins； Lasonolides和Batzellines以及赠款期1-3年发现的化合物。 分离并确定最近确定为胰腺肿瘤细胞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磷核蛋白细胞蛋白细胞蛋白测定法进行筛查海洋提取物，以发现具有对胰腺癌抗肿瘤活性的新型化合物。分离并确定活性化合物的结构。 拟议研究的成功完成将有助于确定新的海洋衍生化合物作为对制药公司开发的潜在许可候选者，以作为抗肿瘤剂的抗肿瘤剂，以防止胰腺癌。