MOLECULAR APPROACHES TO IDENTIFY ANTICANCER LEADS FROM MARINE NATURAL PRODUCTS

鉴定海洋天然产品中抗癌先导化合物的分子方法

• 批准号: 6102634
• 负责人: KENNETH W BLAIR
• 金额: $ 10.92万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6102634
• 关键词: X ray crystallography; antineoplastics; apoptosis; aquatic organism; athymic mouse; bioassay; biological products; biological signal transduction; cell cycle; cell growth regulation; chemical structure function; cooperative study; enzyme linked immunosorbent assay; inhibitor /antagonist; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer pharmacology; nonhuman therapy evaluation; nuclear magnetic resonance spectroscopy; oncogenes; saltwater environment; transcription factor; xenotransplantation

The long term objective of this collaborative research is to discover novel drugs that are useful against the major types of cancer. These are the colon, lung, breast, prostate, and ovarian tumors. Together, these tumors comprise over 70% of human cancers. Cancer is a major cause of death in the USA: over 536,000 Americans die from the disease annually. At present, cancer is treated by surgery, X-ray, radiation, biological therapy and chemotherapy, but these therapies are largely ineffective against the major tumors. There is a critical need to discover effective and selective anti tumor drugs, but this research is severely limited by our lack of understanding of cancer. Our work focusses on the development of antitumor drugs that affect some of the more recently discovered targets and/or processes that are unique or present at different levels in tumors rather than normal tissue. The primary and secondary screens employed by the Oncology Research Program (ORP) at Sandoz are aimed at potentially important oncogene targets. Singly or in various combinations, these oncogenes are found in the majority of common tumors. This approach is different from the more traditional "cytotoxicity-based" cancer drug discovery programs. Compounds found to be active in the primary and secondary screens will be further examined using a battery of human tumor lines that are used for in vitro cytotoxicity assays and as xenografts in nude mice for in vivo antitumor experiments. The diversity of natural products provide a rich opportunity to discover novel antitumor agent classes. These molecules will be produced from extracts of a variety of marine organisms by our University collaborators. Purification of these complex mixtures will be guided by the assays described herein. The assays can efficiently direct the isolation of potentially important lead compounds and structure/activity studIes, thus providing an effective framework for cancer drug discovery and development. To complement the natural product screening program, an active rational drug development program is also in place in the ORP. NMR and X-ray studies on target proteins can provide structural information that can direct the design of candidate drugs. Compounds discovered by screening can also be modified as a result of modeling studies on these structures.

这项合作研究的长期目标是发现 可用于对抗主要类型癌症的新药。这些都是 结肠癌、肺癌、乳腺癌、前列腺癌和卵巢肿瘤。在一起，这些 肿瘤占人类癌症的70%以上。癌症是一个主要原因 美国的死亡人数：每年有超过 536,000 名美国人死于这种疾病。 目前，癌症的治疗方法有手术、X射线、放射线、生物治疗等。 疗法和化疗，但这些疗法基本上无效 对抗主要肿瘤。迫切需要发现有效的 和选择性抗肿瘤药物，但这项研究受到严重限制 我们对癌症缺乏了解。我们的工作重点是 抗肿瘤药物的开发影响了一些最近的疾病 发现的目标和/或进程是唯一的或存在于 肿瘤组织中的水平与正常组织中的水平不同。 肿瘤学研究采用的初级和次级屏幕 Sandoz 的计划 (ORP) 针对潜在的重要致癌基因 目标。这些癌基因单独或以各种组合存在于 大多数常见肿瘤。这种方法不同于更多 传统的“基于细胞毒性”的癌症药物发现计划。 在初级和次级筛选中发现具有活性的化合物将 使用一组人类肿瘤细胞系进行进一步检查 用于体外细胞毒性测定和裸鼠异种移植 体内抗肿瘤实验。 天然产物的多样性提供了丰富的发现机会 新型抗肿瘤剂类别。这些分子将由 我校多种海洋生物提取物 合作者。这些复杂混合物的纯化将遵循 本文描述的测定。该测定可以有效地指导 分离潜在重要的先导化合物和结构/活性 研究，从而为癌症药物发现提供有效的框架 和发展。 为了补充天然产物筛选计划，积极理性的 ORP 中也有药物开发计划。核磁共振和 X 射线 对目标蛋白的研究可以提供结构信息 指导候选药物的设计。筛选发现的化合物 也可以作为对这些结构的建模研究的结果进行修改。