臺灣博碩士論文加值系統

自1982年起，癌症即為台灣地區十大死因之首，現已成為疾病死亡之主要原因之一，其中肺癌的死亡率近年來無論於男性或女性皆高居癌症死亡原因前二位，且台灣地區肺癌死亡率的增加速度亦有逐年上升之趨勢；雖然現有之外科手術、放射線治療等方式不斷進步，以及不斷的有新穎的化學治療藥物被發展出來，包括許多天然植物的萃取物如紫杉醇、常春花鹼類藥物、以及喜樹鹼類藥物，但化療藥物對於病人所產生的副作用以及藥物所具有的潛在抗藥性，仍為抗癌藥物發展受阻的重要原因。
鬼臼毒素 (podophyllotoxin) 原為自天然植物所萃取之天然藥物，對於細胞骨架microtubule具有很高的去穩定化作用，造成細胞無法正常分裂並使細胞週期停止於細胞分裂期，最後造成細胞凋亡 (apoptosis)。鬼臼毒素在早期便已被作為藥物使用，但因其對於正常細胞以及癌細胞的毒殺選擇性較不佳，又因其使用後所造成的強烈副作用，導致鬼臼毒素無法被使用在臨床癌症的治療上。
Ching001為中研院化學所李文山博士所發展，針對鬼臼毒素的結構進行修飾後所產生的鬼臼毒素衍生物，在本篇實驗中發現，新穎的鬼臼毒素衍生物Ching001對於不同肺癌細胞株皆有相當高的毒殺作用，在低濃度處理時，對於正常肺細胞則無明顯之細胞毒性。而Ching001的作用機轉，主要也是作用於細胞骨架microtubule上，造成microtubule的聚合受到抑制並進一步增加不穩定性，使肺癌細胞無法順利進行細胞分裂，並使細胞週期停止於G2/M期，如再持續以Ching001處理肺癌細胞，則會進一步影響細胞內之訊息傳遞，降低細胞凋亡抑制蛋白Bcl-2之表現量，並活化細胞凋亡所需之蛋白酶caspase-9，造成細胞走向細胞凋亡，而達到其抑制肺癌細胞生長增殖並造成細胞毒殺作用之能力。再者我們亦發現Ching001會藉由減少Rac、Rho等訊息傳遞之表現量而使細胞骨架actin filament的結構發生改變，失去filopodium或lamellipodium等促進細胞移動能力之外表型態，並於in vitro實驗中發現可以有效的抑制具有高度轉移潛力的肺癌細胞株CL1-5之轉移能力。在動物實驗中，給予2 mg/kg Ching001治療的裸小鼠其腫瘤之生長也明顯受到抑制達15天之久，並於裸小鼠之血液、生化檢查以及組織切片染色中亦發現，Ching001對於裸小鼠之正常生理功能並不具有明顯的傷害或引發免疫反應，並於腫瘤切片中可觀察到細胞凋亡發生，且實驗期間裸小鼠之體重亦維持於正常範圍內。
根據以上實驗結果，我們認為此一新穎的鬼臼毒素衍生物Ching001對於正常肺細胞與肺癌細胞具有專一性之毒殺作用，並且對於裸小鼠中能有效抑制腫瘤生長，並無產生嚴重生理損害以及造成嚴重副作用，相當具有潛力可以發展成為新穎的癌症用藥。且其對於肺癌細胞的轉移抑制能力，亦具有潛力發展成為抑制肺癌細胞轉移的新穎藥物。

Since 1982, cancer had been the leading cause disease of death in Taiwan, and the mortality of lung cancer has risen most dramatically in both men and women. Recently, the improvement in surgical and radiotherapeutic remedy, and more and more chemotherapy drugs including many potential anti-cancer drugs investigated from nature plant such as Taxol, Vinorelbin, and Camptothecin had been developed. However, the serious side effects and the potent in drug resistance of these drugs, still remain difficult for their development as anti-cancer drugs.
Podophyllotoxin is a nature compound purified from Podophyllum peltatum. It has strong polymerization inhibition ability toward the cell skeleton microtubule. It prevents the cell from normal mitosis and causes G2/M arrest of the cell, finally results in cell apoptosis. Podophyllotoxin had been used as medicine in different countries for thousand of years. However, its poor selectivity to normal/tumor cells and serious side effects after drug treatment prevent it from the usage as anti-cancer drugs.
Ching001, a podophyllotoxin derivatives developed from Dr. Wen-Shan Li at Institute of Chemistry of Academia Sinica in Taiwan. Ching001 was modified for the purpose to be a potential anti-cancer drug. In the present study, we found that novel podophyllotoxin derivative Ching001 had highly cytotoxicity toward different lung cancer cell lines, whereas Ching001 showed low cytotoxicity to the normal lung cell line. In addition, it prevented lung cancer cell from mitosis by inhibiting the polymerization of microtubule and causing cell cycle arrest at G2/M phase. These events eventually led to apoptosis through inhibition of the expression of anti-apoptosis factor Bcl-2 and activation of the expression of apoptosis protease caspase-9. Importantly, Ching001 could effectively inhibit the highly metastasis potential lung cancer cell line CL1-5 through inhibit actin filament construction signaling factors Rac and Rho to inhibit the filopodia or lamellipodia construction. In migration assay experiment, we proved that Ching001 treatment could inhibit the cell from migration in vitro. In the animal model test, 2 mg/kg Ching001 treatment could apparently inhibit the tumor growth for 15days and the effect was stronger than Taxol treatment at same dosage. The hematology and biochemistry tests of nude mice blood samples as well as tissue staining indicated that Ching001 treatment did not distinctively influence the normal function of vitality in animal model. In addition, tumor tissue staining showed that after Ching001 treatment, it induced apoptosis of tumor cells and led to tumor nodule shrinkage.
According to the experiments described above, we believed that novel podophyllotoxin derivative Ching001 will be a potential anti-cancer drug. It may be a good anti-metastasis agent as well.

壹、中文摘要………………………………………………. 1
貳、英文摘要………………………………………………. 3
叁、緒論
一、研究背景與文獻論述………………………………………... 5
(一)、鬼臼毒素及其衍生物的發展………………………………. 5
1.天然植物萃取物於臨床抗癌用藥的發展…………................. 5
2.鬼臼毒素(podophyllotoxin)之發現………………………….... 6
3.鬼臼毒素之應用……………………………………................. 6
4.鬼臼毒素之結構……………………………………................. 7
5.鬼臼毒素之抗癌作用機制……………………………………. 7
6.鬼臼毒素於臨床應用之缺點………………………................. 8
7.鬼臼毒素衍生物之發展……………………………................. 9
8.各種不同鬼臼毒素衍生物之作用機轉……………................. 10
9.鬼臼毒素衍生物於癌症治療之臨床應用…………................. 11
10.新穎鬼臼毒素衍生物 ─ Ching001………………................. 12
(二)、癌症轉移抑制劑的發展……………………………………. 13
1.癌症的轉移……………………………………………………. 13
2.細胞骨架actin filament與癌細胞轉移………………………. 13
3.癌細胞轉移抑制劑……………………………………………. 14
二、研究目標……………………………………………............... 16
肆、研究材料與研究方法
一、研究材料……………………………………………………... 17
二、研究方法……………………………………………………... 18
1. 細胞培養 (Cell Culture)…………………………………...… 18
2. 藥物之細胞毒性分析 (Compound Cytotoxicity Assay)…… 18
3. 細胞週期分析 (FLOW Cytometry)…………………………. 18
4. DNA Ladder Assay……………………………………….....… 19
5. 西方墨點法 (Western Blot)……………………………….… 20
6. 免疫細胞染色法 (Immunocytochemistry)………………….. 20
7. 分子模擬對接 (Molecular Docking)....................................... 21
8. 細胞轉移能力分析 (Trans-well Migration Assay)………….. 22
9. 動物實驗 (Animal Model Test)…………………………....... 22
10. HE-staining (Haematoxylin-Eosin staining)……………….... 23
伍、實驗結果
一、藥物Ching001對於肺癌細胞之細胞毒性…………………. 25
二、藥物Ching001對於細胞週期的影響………………………. 25
三、藥物Ching001對於肺癌細胞凋亡的檢驗………………..... 26
四、藥物Ching001對於細胞骨架microtubule的影響…...……. 27
五、藥物Ching001對於肺癌細胞actin骨架調控蛋白的影響… 28
六、藥物Ching001對於肺癌細胞的轉移能力測試…………….. 28
七、藥物Ching001於動物模式中的效力………………………. 29
陸、討論……………………………………………………. 31
柒、未來工作………………………………………………. 38
捌、附圖……………………………………………………. 40
玖、附表……………………………………………………. 61
拾、文獻總整………………………………………………. 62

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