當歸萃取物與抗肝腫瘤西藥之體內外協同作用之探討與抗癌機制之研究

韓鴻志
慈濟大學
肝癌是世界上最常見的惡性腫瘤之一，目前是國人十大死亡原因的第一位。長久以來的研究顯示，單一藥物對於肝癌的治療效果有限，不論是5-fluorouracil (5-FU)、doxorubicin、cisplatin、etoposide等臨床用藥其反應率大都介於10-30%。因此合併療法 (combination chemotherapy) 是目前研究學者及臨床試驗致力的方向。可惜的是，上述臨床藥物合併治療的結果顯示，腫瘤的反應率比起個別的臨床試驗並沒有顯著的提升。因此尋求中草藥治療或併同化療藥物，是目前歐美及我國治療癌症的趨勢。已有證據顯示，有些中草藥萃取物合併臨床用藥在對抗肝瘤具有協同作用 (synergism)，可以透過提高免疫力或造成細胞凋亡來增加癌細胞生長抑制，且不造成明顯細胞或動物毒性。近年來的研究結果發現，甲基化 (methylation) 是重要的上位基因現象 (epigenetic phenomena)，通常會導致基因沉寂 (gene silence) 現象。甲基化狀態的改變與基因的異常表達相關。已知MGMT啟動子高甲基化 (MGMT promoter hypermethylation) 而失活可能是肝瘤形成過程的重要事件，在 MGMT 轉入肝癌細胞的實驗中發現，MGMT 蛋白質活性的回復會抑制 BCNU 等烷化劑類藥物所造成的蛋白質泛素化降解途徑作用。但值得注意的是，MGMT 蛋白質的過度表現是腫瘤產生抗性的主要原因之一，由於腫瘤抗藥性的產生是目前臨床藥物普遍反應率不佳的主要原因，因此利用中草藥抑制 MGMT 的表現可能有助於臨床藥物的合併治療。在我們先前的實驗發現，從當歸丙酮層萃取而來的純物質n-Butylidenephthalide (BP) 會可引起人類惡性腦腫瘤細胞株 DBTRG 及大白鼠惡性腦腫瘤細胞株RG2等細胞株的細胞週期停滯於G0/G1 時期，並引發細胞凋亡。初步實驗結果顯示，BP 會造成 GBM 及大白鼠腦瘤細胞株 RG2 內 MGMT 基因啟動子甲基化程度增加，進而抑制其蛋白質表現 ，因此推論 MGMT 可能是 BP 的目標基因，也推測此抗癌機轉可以應用於西藥的合併治療。
關鍵字：協同作用；甲基化；微陣列分析

To Investigate the Synergic Effect of Angelicae Sinensis Extract with Current Chemotherapy in Human Hepatocellular Carcinoma

Harn, Horng-Jyh
Tzu Chi University
Hepatocellular carcinoma (HCC) is relatively uncommon in Northern European countries, accounting for only 3-5% of all cancers, but it is one of the most frequent cancers worldwide. The main curative therapies for cancer surgery and radiation can be only successful in general if the cancer is found at an early stage and is localized. Currently conventional chemotherapy for treatment of the advanced tumors, although quite effective, has been associated with toxicities to normal tissue and organs, which is still a major dose limited factor. And chemoresistance is another major obstacle for successful treatment of cancer. It is clear that new therapeutic options are necessary. Chinese medicine provides a rich poor of novel and efficacious agents for treatment a variety of diseases, especially which could not be cured by western medicine. It was evidence that Chinese herbs had synergic effect with current chemotherapy in treatment hepatocellular carcinoma. To study the epigenetics of some kind of genes is essential to realize the carcinogenesis of HCC. O6-methylguanine-DNA methytransferase (MGMT) was participated in the process of DNA repair and cell cycle regulation. Mammalian MGMT can be modestly induced by a variety of DNA damaging agents, by infection, and by partial hepatectomy, which observed parallel increases in MGMT and specific mRNA again suggesting regulation of MGMT expression at the level of MGMT transcription.
關鍵字：methylation；synergistic；n-Butylidenephthalide