MOLECULAR APPROACHES TO IDENTIFY ANTICANCER LEADS FROM MARINE NATURAL PRODUCTS

这项合作研究的长期目标是发现 对主要类型的癌症有用的新药。这些是 结肠、肺、乳腺、前列腺和卵巢肿瘤。加在一起，这些 肿瘤占人类癌症的70%以上。癌症是导致癌症的主要原因 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、放射治疗、生物治疗。 治疗和化疗，但这些疗法大多无效 对抗主要的肿瘤。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 影响某些新药的抗肿瘤药物的研究进展 发现的目标和/或进程是唯一的或存在于 在肿瘤组织而不是正常组织中有不同的水平。 肿瘤学研究所采用的初级和次级筛查 Sandoz的计划(ORP)针对的是潜在的重要癌基因 目标。这些癌基因单独或以不同的组合存在于 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”的抗癌药物发现计划。 在初级筛选和次级筛选中发现的活性化合物将 使用一组人类肿瘤细胞株进行进一步检查 进行体外细胞毒性试验和裸鼠移植瘤的细胞毒试验 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 新型抗肿瘤药物类。这些分子将从 我校多种海洋生物提取液 合作者。这些复杂混合物的提纯将由 本文所述的检测方法。这些检测方法可以有效地指导 潜在重要先导化合物的分离及其结构/活性 研究，从而为癌症药物的发现提供了一个有效的框架 和发展。 为了补充天然产品筛选计划，积极的理性 药物开发计划也在ORP中到位。核磁共振和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。通过筛选发现的化合物 也可以作为对这些结构的建模研究的结果进行修改。

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.