2011-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/660012摘要：惡性腫瘤是台灣十大死因之冠，目前主要的治療方式是手術切除輔以化學或放射線治療。但腫瘤轉移、藥物的副作用以及抗藥性的產生仍是目前的最大挑戰，未來期望癌症治療藥物能更有效、更專一，不傷害正常細胞且降低副作用。目前許多臨床使用的抗癌藥物來自於天然物，而本實驗室一向致力於由天然萃取物中研發新的抗癌藥物。萃取自中藥石斛的成分moscatilin具有抗血小板凝集、毒殺癌細胞和抑制腫瘤細胞生長以及抗發炎的作用，極具發展潛力成為新的抗癌藥物。本計畫將與中國醫藥研究所沈建昌教授合作，主要目標為:1.對moscatilin的結構加以修飾，得到具有抗癌症轉移作用之衍生物。2.利用各種生化以及細胞實驗，如: migration, invasion, Western blot, RT-PCR, SiRNA, EMSA, flow cytometry, ELISA, luciferase assay and zymography來研究衍生物抗轉移作用的機轉，並委託MDS公司做SpectrumScreen®以找出更多的藥物作用點 3.利用已建立的動物模式human tumor xenograft model和spontaneous metastasis model來確定藥物在動物體內抗腫瘤生長以及抗轉移的效果。最後我們也將委託財團法人生物技術開發中心進行毒理實驗，以及委託世宬公司建立藥物的藥物動力學資訊。經由以上的實驗，可以評估moscatilin衍生物促腫瘤細胞凋亡以及抗腫瘤轉移的作用，並在動物模式加以確認效果。我們希望本計畫能在抗癌新藥研發以及臨床治療上有所貢獻。<br> Abstract: According to the statistical data of DOH, cancer is the leading cause of death in Taiwan. The standard treatments of cancer include surgery, chemotherapy and radiation therapy. However, metastasis, drug-resistance and the side-effects of chemotherapy are major events to cause mortality of cancer treatment. It is of hopes that the future cancer treatment drugs will be more effective and specific, to be highly selective in killing cancer cells without harming normal systems, thereby reducing the side effects. Till now, there are various anticancer drugs which derived from natural products. Therefore, we are interested in the development of the natural products as a new source of anti-cancer drug.Our previous reports demonstrated that moscatilin, isolated from traditional Chinese medicine Dendrobrium loddigesii, inhibits platelet aggregation, exerts potent cytotoxic effects against stomach and lung cancer, has anti-proliferative effect in various cancer cells (e.g. colon, prostate, breast cancer), and exhibits anti-inflammatory effect in macrophages. These evidences indicate that moscatilin may have potential to be a new anticancer drug. This project will cooperate with Prof. Chien-Chang Shen, National Research Institution of Chinese Medicine. Prof. Shen will provide a series of derivatives that base on the structure of moscatilin to reduce side effects of parent compound and increase potency of anti-cancer effect.The specific aims of this project include the following: Specific Aim 1 is design of potential anti-metastatic activity of moscatilin analogs. The first step in the drug discovery effort was the structure-based design. Aim 2. Follow up primary screen of moscatilin analogs with anti-metastatic biochemical and cell based assays, such as migration, invasion, Western blot, RT-PCR, SiRNA, EMSA, flow cytometry, ELISA, luciferase assay and zymography, and also perform the enzyme screening (SpectrumScreen®) by MDS Pharma Services, which could find out more targets of these active compounds. Aim 3. The establishments of optimized animal models are crucial for the success of moscatilin analogs. To understand complex biological phenomena and the process of disease development, it requires the application of animal model and proper data analysis. We will confirm the in vivo anti-cancer and anti-metastatic efficacy of drugs in human tumor xenograft model and spontaneous metastasis model, respectively. Finally, we will proceed toxicological experiments by Development Center of Biotechnology, and establish the pharmacokinetic profile of the drugs by Rosetta Pharmamate Co. Ltd.Based on these assessments, the apoptotic and anti-invasive potential of moscatilin series compounds will be elucidated and the potency will be confirmed in animal models. We hope that this project could contribute to the new drug development and clinical therapy.環山石斛 moscatilin乳癌轉移moscatilinbreast cancermetastasis