新穎性秋水仙素衍生物AD1對食道癌之作用影響

The effect of a novel colchicine derivative AD1 on human esophageal cancer

李俐慧(Li-Hui, Lee)

指導教授 ： 劉俊仁

共同指導教授 ： 陳裕仁(Yu-Jen Chen)

臺北醫學大學/醫學科技學院/醫學檢驗暨生物技術學系/碩士(2012年)

https://doi.org/10.6831/TMU.2012.00184

摘要

根據民國99年行政院衛生署公布的國人十大死因，癌症已連續29年蟬聯十大死因榜首。其中，食道癌為高度惡性且預後不佳的疾病，在全世界癌症好發排行中排名第七位，五年存活率甚至超低於20 %。更令人擔憂的是，在台灣因食道癌死亡的年齡已呈現年輕化趨勢，引發國人健康甚鉅，值得高度的重視。因此，藉由發展新一代化學治療藥劑，期盼能夠提供食道癌患者治療的新契機。
抗有絲分裂製劑 (antimitotic agent)已被證實能有效地使用在抗癌上，這類藥物的作用機轉主要是干擾微小管的動態平衡，導致微小管的結構受到破壞，進而阻礙癌細胞的有絲分裂過程，達到抑制細胞週期的進行以造成抑制癌胞生長。其中，微小管抑制劑「秋水仙素」，雖然其藥物特性具有抑制腫瘤細胞的效果，不過毒副作用卻限制其臨床應用發展，因此目前在臨床上的發展主要是應用在治療急性痛風 (gout)。本研究希望藉由開發新穎性秋仙水素衍生物AD1，期望能減低生物毒性作用，並維持其藥物特性以增強抗癌活性。
在本研究的抗癌活性篩選實驗中發現，AD1對於不同類型食道癌細胞株具有優異的抗癌活性。在本研究中，我們證實AD1所引發食道癌細胞死亡形式並不屬於典型的細胞凋亡，而是屬於非典型有絲分裂風暴的細胞死亡型態。在AD1誘導食道癌細胞進行死亡的過程中，因AD1會引起染色體不正常分離，進而形成不規則形的細胞核與具有多核的巨形細胞，此現象屬於有絲分裂風暴的典型特徵。另外，我們也證實AD1可調節細胞週期相關分子之表現而導致食道癌細胞的細胞週期停滯在G2/M phase。鑑於此週期具有放射線敏感性，在動物實驗的結果中發現AD1合併放射線治療確切能夠有效減低老鼠腫瘤體積的生長。
針對秋水仙素有效成份合成的化合物AD1，在本研究中發現具有藥物發展的潛力。並藉由初步體外實驗結果，期望將來AD1能被開發成為有效的抗癌藥物，甚至可能運用在作為食道癌治療的輻射增敏劑發展上。

關鍵字

食道癌、微小管、秋水仙素、新穎性秋水仙素衍生物AD1、有絲分裂風暴、輻射

並列摘要

According to the report of Department of Health in 2010, cancer has been listed as the number one cause of death in Taiwan for 29 consecutive years. Among all these cancers,
Esophageal cancer, the seventh leading cause of cancer mortality worldwide, was unresectable with dismal prognosis while diagnosing. Its 5-year survival rate was under 20 % and the median age of death caused by it was getting younger and younger. Clearly, development of new effective therapeutics for esophageal cancer remains the critically important issue in clinical practice.
The majority of antimitotic agents have been proven to be with anticancer activity. The main anticancer mechanism of these agents is to interfere in the dynamic equilibrium of
microtubules, damage the structure of microtubules, prevent cancer cell from starting mitosis and eventually, suppress the tumor growth by controlling the cell cycle. Colchicine, one of the microtubule inhibitor, was currently used on treating gout. Although the medicinal property of colchicine could function as anticancer agent, the development of its clinical application was limited by its toxicity. To overcome this limitation and improve therapeutic window, a novel colchicine derivative AD1 was developed and evaluated on cancer therapy, whose toxicity of
colchicine had been decreased.
In this study, we learned that AD1 had excellent antitumor activity against esophageal cancer cell. While treating with AD1, giant multinucleated cells were observed in all the drug-treated esophageal cancer cell lines. It indicated, instead of typical apoptosis, the death of
esophageal cancer cell cause by AD1 treatment was part of mitotic catastrophe. Because AD1 could regulate cell cycle-related molecules expression, further combination of AD1 with ionizing radiation was also tested in this study. In vivo human esophageal cancer xenograft model showed that there was a synergistic antitumor activity while combining AD1 with radiation.
In conclusion, this study showed that AD1 might be a potent and novel therapeutic agent against esophageal cancer and play a role in radiation sensitization.

並列關鍵字

Esophageal cancer, AD1, Colchicine, Mitotic catastrophe, Chromosome, Radiation

參考文獻

1. 99 年死因簡報. 行政院衛生署 2010.

6. 葉坤輝: 食道癌之化學與放射療法. 當代醫學 1998, 25:3.

2. Tae Jung Kim MHYk, Kyung Won Lee, Moon Soo Kim: Multimodality Assessment of esophageal cancer-preoperative staging and monitoring of response to therapy. RadioGraphics 2009, 29:19.

4. Melhado RE, Alderson D, Tucker O.: The Changing Face of Esophageal Cancer. Cancers 2010, 2:1379-1404.

Orringer, Raymond U. Osarogiagbon, James A. Posey, Aaron Keswani, Lawrence R. Kleinberg, W. Michael Korn, A. Craig Lockhart, Mary F., Glasgow JAH, Wayne L. Hofstetter,