ANTICANCER AGENTS FROM UNIQUE NATURAL PRODUCTS SOURCES

描述：(申请人描述) 这是NCDDG于1995年9月授予的67786加元的首次竞争性续签。该项目的目标保持不变，目的是从各种天然产品来源中发现和开发新的抗癌药物。该计划的基本主题是将从栖息于独特生态位的有机体中发现新的具有生物活性的天然产物与机制导向的癌症生物学相结合。尽管公司合作伙伴更改了名称，但核心小组的组成基本上与原始申请中的相同。美国鲤鱼的Lederle实验室现在是Wyeth-Ayerst Research(W-AR)。在战争中有一些人员的更替，并增加了一个药物化学小组，以促进药物开发研究。此外，还增加了四个新的分包合同，以便利获得更多种类的生物。 在第一个赠款期间，在确定药物开发和临床研究候选人的目标方面取得了重大进展。在最初的三年里，超过4900种生物的提取物在W-AR的分析中进行了活性筛选。对这些提取物在包括活体动物模型在内的二级检测中的调查，导致三个项目被指定为发现线索。这些是来自海绵Cymbasela sp.的半胱氨酸，来自真菌AspergillusUstus的自体半胱氨酸，以及来自海绵Zyzzya fuliginasa的makaluvamines。半星人已被指定为W-AR的开发项目和一个医疗团队 化学家已经被指派到这个项目中。在被指定为开发项目之前，austocystins和makaluvamine正在接受进一步的体内测试。关于这些项目的详细讨论载于进度报告各节。

DESCRIPTION: (Applicant's Description) This is a first competitive renewal of NCDDG grant CA 67786, which was awarded in September 1995. The goal of the project remains unchanged and is to discover and develop novel anticancer agents from a variety of natural products sources. The underlying theme of this program is to integrate discovery of novel biologically-active natural products from organisms that inhabit unique ecological niches with mechanism-directed cancer biology. The composition of the core group remains essentially the same as in the original application although the corporate partner has changed names. Lederle labs of American Cyanimid is now Wyeth-Ayerst Research (W-AR). There has been some turnover in personnel at WAR, and a Medicinal Chemistry group has been added to facilitate drug development studies. Additionally, four new subcontracts have been added to facilitate access to a greater diversity of organisms. Significant progress has been made in the first grant period towards the goal of identifying candidates for drug development and clinical study. In the first three years, extracts of more than 4,900 organisms were screened for activity in assays at W-AR. Investigation of these extracts in secondary assays, including in vivo animal models, resulted in designation of three projects as discover leads. These are the hemiasterlins from the sponge Cymbastela sp., the autocystins from the fungus Aspergillus ustus, and the makaluvamines from the sponge Zyzzya fuliginasa. The hemiasterlins have been designated a development project at W-AR and a team of medicinal chemists has been assigned to the project. The austocystins and makaluvamines are undergoing further in vivo testing before designation as development projects. Detailed discussions of these projects are presented in the progress report sections.