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: 6203187
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-09-17 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6203187
• 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; drug discovery /isolation; 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 用于治疗主要类型癌症的新药。这些是 结肠、肺、乳腺、前列腺和卵巢肿瘤。所有这些 肿瘤占人类癌症的70%以上。癌症是一个主要的原因 美国的死亡：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、生物治疗、放射治疗 治疗和化疗，但这些治疗在很大程度上是无效的 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 抗肿瘤药物的发展，影响一些最近 发现的目标和/或进程是唯一的或存在于 在肿瘤组织中的水平不同，而不是正常组织。 肿瘤学研究所采用的一级和二级筛选 Sandoz的ORP项目旨在研究潜在的重要致癌基因 目标的这些致癌基因单独或以各种组合存在于 大多数常见的肿瘤。这种方法不同于 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作为裸鼠中的异种移植物， 体内抗肿瘤实验。 天然产品的多样性提供了丰富的机会， 新的抗肿瘤剂类别。这些分子将由 我们的大学从各种海洋生物中提取了 合作者这些复杂混合物的纯化将由以下指导： 本文所述的测定。该测定可以有效地指导 潜在重要先导化合物的分离和结构/活性 研究，从而为癌症药物发现提供了有效的框架 发展先行者的要求 为了补充天然产品筛选计划， 药物开发计划也在ORP中。NMR和x-射线 对靶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进行建模研究的结果进行修改。