Natural Product Antitumor Inducers of Apoptosis

描述：(申请人提供)天然产品包括 临床上有用的抗肿瘤药物。这个项目的总体目标是找到 并识别可以操纵蛋白质和其他生物功能的小分子 与癌症相关的受体。回答与以下相关的关键问题 细胞毒性化合物的作用机制和作用部位是目前迫切需要的。 从化合物发现到临床试验的早期进展。真的 最有可能引起人们兴趣的新型化疗药物是 显示出抗实体瘤活性的细胞毒性或细胞抑制化合物 还针对事件序列中的新干预点 致癌作用。诱导转化细胞凋亡的天然产物 肿瘤细胞增殖可能导致肿瘤细胞特异性抑制剂的产生 作为癌症化疗药物有用的药物。药物诱导的细胞凋亡 涉及由一系列基因和基因介导的细胞周期特异性事件 包括P53和Bcl2在内的可能构成癌症新靶点的产物 化疗。细胞凋亡在急性髓细胞白血病的临床转归中具有重要意义 癌症化疗，不仅是为了阻止肿瘤的生长，也是为了固体 通过疏导肿瘤细胞的凋亡来减少肿瘤的消退 有问题的炎症反应。 纯净的细胞毒性和细胞抑制天然产物将从 从具有独特海洋生物多样性的地点收集的无脊椎动物 生物测定引导的提纯。活性化合物的优先顺序将基于 抗HCT-116(结肠癌)、CCRF-CEM(T细胞白血病)、MCF-7的活性 (乳房)、PC-3(前列腺癌)、SK-Mel-5(恶性黑色素瘤)、A549(肺 癌)和HL-60(早幼粒细胞)肿瘤细胞株。优先考虑的细胞毒性 还将评估也能诱导PC-3和MCF-7细胞凋亡的化合物 进一步通过细胞流式细胞术和使用DNA微阵列的药物图谱 确定与细胞周期停滞相关的基因的技术 药物诱导的细胞凋亡事件。由此产生的有希望的新线索 评估将推进到动物模型的体内试验，以确定 它们在抗癌新药开发中的潜在作用 对人类实体肿瘤有积极作用。

DESCRIPTION: (provided by applicant) Natural products are represented among clinically useful antitumor agents. The general goal of this project is to find and identify small molecules that can manipulate function of proteins and other receptors relevant to cancer. Answers to critical questions related to mechanism and site of action of cytotoxic compounds are now desired much earlier in the progression from compound discovery to clinical trial. Truly novel chemotherapeutic agents that are most likely to attract interest are cytotoxic or cytostatic compounds that exhibit activity against solid tumors and also target novel points of intervention in the sequence of events in oncogenesis. Natural products that induce apoptosis in transformed proliferating tumor cells may lead to tumor cell-specific suppressive agents that are useful as cancer chemotherapeutic drugs. Drug-induced apoptosis involves cell-cycle specific events mediated by a family of genes and gene products including p53 and Bcl-2 that may constitute a novel target for cancer chemotherapy. Apoptosis has important implications in the clinical outcome of cancer chemotherapy, not only for arresting tumor growth, but also for solid tumor regression by channeling the disposal of apoptotic tumor cells without problematic inflammatory responses. Pure cytotoxic and cytostatic natural products will be isolated from invertebrates collected from sites of unique marine biodiversity based on bioassay-guided purification. Active compounds will be prioritized based on activity against HCT-116 (colon tumor) and CCRF-CEM (T-cell leukemia), MCF-7 (breast), PC-3 (prostate), SK-MEL-5 (malignant melanoma), A549 (lung carcinoma), and HL-60 (promyelocytic) tumor cell lines. Prioritized cytotoxic compounds that also induce apoptosis in PC-3 and MCF-7 will be evaluated further by cell flow cytometry and drug profiling using DNA-microarray technology to determine the involvement of genes in cell-cycle arrest related to drug-induced apoptotic events. Promising new leads that emerge from this evaluation will be advanced to in vivo trials in animal models to ascertain their potential usefulness as leads in development of novel anticancer drugs active against human solid tumors.