2011-05-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/643812摘要：根據衛生署98 年的統計資料顯示，惡性腫瘤連續28 年蟬聯國人的第一死因，其中，結腸直腸癌又高居癌症死因的第三位。當腫瘤已經無法藉由手術移除，或是發生轉移時，給予全身性的化療藥物以及標靶藥物可增加病人的存活率。在研發癌症的用藥中，常以中草藥的成分作為新藥開發的來源，希望能師法自然，從天然物中找到抑制腫瘤細胞生長的化學結構。Antofine 是純化自植物(Cynanchum paniculatum)中的生物鹼，主結構為phenanthroindolizidine，且已被證實有顯著的抗癌作用，但同時因其易通過血腦屏障也造成中樞神經的毒性。在北卡羅來納大學教堂山分校任教的李國雄院士，基於此結構合成了一系列YXM 衍生物，期能篩選出具有抗癌藥潛力且較無副作用之化合物。目前實驗結果顯示，YXM110 在眾多衍生物中，對於多株人類癌細胞皆展現了相當優秀的抑癌能力，其GI50 低至10-9M。更因在YXM110 結構上的修飾使得水溶性增加，進而減少了原始天然物結構對於CNS 所造成的副作用，因此我們認為YXM110 極具前瞻性，很有機會作為先導藥物。初步研究已觀察出 YXM110 在HCT116 這株結腸直腸癌細胞上抑癌效果最佳，因此目前選定結腸直腸癌細胞株HCT116 作為對象來進行細胞和活體模式的相關實驗，研究YXM110 及其衍生物可能的作用機轉、物化性質、以及在活體中的藥物動力學和安全性。在本計畫所規劃的兩年中，我們將以 YXM110 及其衍生物的最適化作為主要目標，期能找出最佳先導化合物，進而能夠技術轉移，交由國內的法人單位或生技產業承接，繼續完成候選藥物之臨床前試驗。<br> Abstract: Malignant tumor has been the major cause of death in Taiwan for 28 years. Untilnow, researchers are still seeking for better cancer therapies. When tumors are unableto be removed surgically or already undergo metastasis, systemic chemotherapy andtarget therapy become crucial for patient survival. Natural products have always beena profuse database for developing new chemo agents, thus modification from naturalcompounds which exhibit potent antitumor activity could be an effective strategy.Antofine is a phenanthroindolizidine alkaloid purified from Cynanchumpaniculatum which shows excellent antitumor activity. Its cytotoxicity against variouscancer cell lines was already identified by several groups. The CNS toxicity was alsodocumented because of its ability to penetrate blood brain barrier (BBB). Prof. K.H.Lee from Natural Product Research Lab (NPRL) in UNC at Chapel Hill hassynthesized a series of compounds named YXM110 based on antofine with similarpotency. More importantly, they increased hydrophilicity of these compounds to lowerthe CNS toxicity. Our previous data showed that (a) YXM110 exhibited greatestactivity against human colorectal cancer cell line HCT116; (b) YXM110 induced cellcycle arrest and persistent Erk activation in a time- and concentration-dependentmanner; (c) YXM110 analogue, YXM74, inhibited tumor growth in HT29 xenograftmodels; (d) YXM74 has little toxicity in mice. These evidences indicate that YXM110has a great potential to become an anticancer lead compound.AimsThe main purpose of this project is to optimize lead (YXM110), synthesizeanalogues, elucidate their action mechanisms, and evaluate the in vivo anticancerpotency, pharmacokinetics and toxicity in preclinical stage. It will take two years toachieve this goal. In the first year, we will clarify the death type and generalcytotoxicity mechanism and screen all the possible targets of YXM110 analogues byRNA array to figure out the main pathway for anticancer activity. Moreover, thesafety and toxicity of YXM110 analogues will be tested by MTD assay. Based onthese results, NPRL will modify the chemical structures and synthesize derivativeswith better anti-tumor activity and safety. Most importantly, their in vivo anti-tumoractivity will be evaluated in HCT116 xenograft models.In the second year, the lead compound will be chosen from YXM110 analogues.We will establish xenograft models of HCT116 and other cell lines to continuallyestimate the anti-tumor activity and pharmacokinetics of this lead compound. Besides,the early PK and acute toxicity will be monitored by entrusted companies. NPRL willalso keep modifying the structures of YXM110 series to increase potency,physicochemical properties, PK, and lower side effects.ConclusionOnce the best lead compound has been indentified, this candidate will betransfered to a bio-technology company for further development in pre-clinical studiesand clinical trials. Through the academia-industry cooperation, we desire to develop anew anticancer agent for colorectal carcinoma (CRC) or other cancers in Taiwan.小穗苧麻素生物鹼結腸直腸癌細胞生長抑制自噬作用cryptopleurinealkaloidYXM110HCT116anti-proliferationautophagy