KRAMER SCIENTIFIC PROGRAM

克莱默科学计划

• 批准号: 6203318
• 负责人: ROBERT A KRAMER
• 金额: $ 9.68万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6203318
• 关键词: DNA replication; DNA topoisomerases; Fungi; Invertebrata; antineoplastics; aquatic organism; bioassay; biological products; biological signal transduction; cell growth regulation; cell sorting; chemical structure function; clone cells; cytotoxicity; drug discovery /isolation; drug screening /evaluation; enzyme inhibitors; immunomodulators; marine biology; microorganism metabolism; neoplasm /cancer pharmacology; neoplastic cell; tubulin; water microbiology

The objectives of this program are to utilize the Cyanamid Oncology Drug Screen (CODS) to identify and develop structurally novel marine and microbial natural products that have novel mechanisms of action against solid tumors and utility in the treatment of human cancer. This goal is accomplished through the following specific aims: 1. To screen approximately 1,200 marine invertebrate, fungi, and microorganism samples per year, provided by Drs. Ireland, Clardy, Maiese and Andersen. The CODS assay exploits the phenotypic diversity of 26 different human tumor cell lines in order to generate unique activity. 2. To provide biologic support for the bioassay guided purification of active metabolites. This will be achieved either by transferring appropriate cell lines and biochemical assays to the program leaders or can be conducted by this core biological program. 3. To conduct biochemical, gene reporter and flow cytometry studies to characterize the mechanism of action of screening leads. Compounds that act vs. non-validated oncology targets (e.g., signal transduction) or novel targets can be identified. Detailed biochemical studies on known oncologic targets (e.g., topoisomerase, tubulin, DNA) also enable us to identify compounds that act by novel mechanisms against these therapeutically relevant targets. 4. To conduct in vivo studies against a battery of human and murine tumor models to establish the in vivo efficacy of screening leads. 5. To screen for the immune response activity of samples not demonstrating antiproliferative or cytotoxic activity. In collaboration with Immunex, samples are evaluated for activity as immune response regulators that either stimulate the immune response and thereby suppress tumor growth, or that ablate chemotherapy induced myelosuppression. 6. To design and implement preclinical and clinical strategies for development of lead compounds.

该程序的目标是利用氰基肿瘤学 药物筛选（COD）以识别和发展结构新颖的海洋 和具有新型作用机理的微生物天然产品 反对实体瘤和效用在人类癌症治疗中。 该目标是通过以下特定目标实现的： 1。要筛选大约1,200海洋无脊椎动物，真菌和 每年提供的微生物样品，由Drs提供。爱尔兰，克拉迪， Maiese和Andersen。 CODS分析利用表型多样性 为了产生独特的26种不同的人类肿瘤细胞系 活动。 2。为生物测定指导纯化提供生物学支持 活性代谢物。这将通过转移来实现 适当的细胞系和生化测定对计划负责人 也可以由该核心生物学计划进行。 3。进行生化，基因报告基因和流式细胞术研究 表征筛选引线的作用机理。化合物 该行为与未验证的肿瘤学目标（例如，信号 可以确定转导）或新目标。详细的生化 研究已知的肿瘤靶标（例如拓扑异构酶，微管蛋白，DNA） 还使我们能够识别通过新型机制起作用的化合物 针对这些治疗相关目标。 4。进行体内研究针对人和鼠 肿瘤模型以建立筛选铅的体内功效。 5。筛选样品的免疫反应活动 证明抗增生或细胞毒性活性。在 与Immunex合作，将样本评估为活动 免疫反应调节剂，可刺激免疫反应 从而抑制肿瘤的生长，或消融化疗诱导 骨髓抑制。 6。设计和实施临床前和临床策略 铅化合物的开发。