Natural Product Antitumor Inducers of Apoptosis

描述：（由申请人提供）天然产品的代表是 临床上有用的抗肿瘤剂。该项目的总体目标是找到 并识别出可以操纵蛋白质功能的小分子， 与癌症相关的受体。对与以下方面有关的关键问题的回答 现在非常需要细胞毒性化合物的作用机制和位点 从化合物发现到临床试验的早期阶段。真正 最有可能引起兴趣的新的化学治疗剂是 表现出抗实体瘤活性的细胞毒性或细胞抑制性化合物 并在一系列事件中瞄准新的干预点， 肿瘤发生诱导转化细胞凋亡的天然产物 增殖的肿瘤细胞可能导致肿瘤细胞特异性抑制剂 其可用作癌症化疗药物。药物诱导的细胞凋亡 涉及由基因家族介导的细胞周期特异性事件， 包括p53和Bcl-2在内的产物可能构成癌症的新靶点 化疗细胞凋亡在肿瘤的临床结局中具有重要意义。 癌症化学疗法，不仅用于阻止肿瘤生长，而且还用于实体瘤。 通过引导凋亡肿瘤细胞的处置而使肿瘤消退， 有问题的炎症反应。 纯细胞毒性和细胞抑制性天然产物将从 从独特的海洋生物多样性地点收集的无脊椎动物， 生物测定引导的纯化。活性化合物的优先顺序将根据 抗HCT-116（结肠肿瘤）和CCRF-CEM（T细胞白血病）、MCF-7 （乳腺）、PC-3（前列腺）、SK-MEL-5（恶性黑色素瘤）、A549（肺） 癌）和HL-60（早幼粒细胞）肿瘤细胞系。优先细胞毒性 还将评价在PC-3和MCF-7中诱导细胞凋亡的化合物 进一步通过细胞流式细胞术和使用DNA微阵列的药物谱分析 技术，以确定基因参与细胞周期停滞相关 药物诱导的凋亡事件。从这件事中出现的有希望的新线索 评估将推进到动物模型的体内试验，以确定 它们作为开发新型抗癌药物的先导的潜在用途 对人实体瘤有活性。

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.