- 學位論文
利用抗氧化劑改善pegylated liposomal doxorubicin (PLD)誘導之手足症候群及其協同抗癌效用
Amelioration of pegylated liposomal doxorubicin (PLD)-induced hand-foot syndrome by antioxidants with synergistic anti-tumor effect
摘要
Pegylated liposomal doxorubicin (PLD)為doxorubicin以polyethylene glycol (PEG)修飾的微脂體包覆劑型常用於卵巢癌及乳癌的治療，相較於傳統的doxorubicin，PLD可以降低心臟毒性、增加藥物體內半衰期及迅速滲透腫瘤組織的效果，但由於PLD長時間的血液循環，會從肢端微血管滲出累積在手足部位細胞釋放出doxorubicin，在細胞內產生活性氧類(reactive species oxygen, ROS)增加氧化壓力引發細胞凋亡，導致嚴重的手足症候群副作用。 因此本研究目的在於探討是否能藉由抗氧化劑降低細胞內doxorubicin-induced ROS的產生來達到預防PLD所造成之手足症候群，同時也觀察抗氧化劑是否與doxorubicin具有協同作用增進患者在癌症治療上的效果。 本研究以白藜蘆醇、烏藜蘆醇、薑黃素以及牛樟芝萃取物四種抗氧化劑作為研究對象。實驗分為兩部分（一）以3T3纖維母細胞作為手足的正常細胞模式，評估這四種抗氧化劑在預防及降低PLD所造成之手足症候群的能力，（二）以MCF-7乳癌細胞模式探討抗氧化劑與doxorubicin的協同抗癌作用能力。實驗結果顯示，在投予doxorubicin前事先投予白藜蘆醇，對3T3纖維母細胞有最佳的抗氧化作用其次為薑黃素，顯示此二種抗氧化劑具有預防手足症候群產生的效果。若將抗氧化劑與doxorubicin同時投予則以牛樟芝萃取物的抑制doxorubicin-induced ROS之效果最佳，具有可降低副作用產生之效果。此外，白藜蘆醇及薑黃素與doxorubicin一起投予MCF-7乳癌細胞時比單獨使用doxorubicin更能降低癌細胞存活率，顯示白藜蘆醇和薑黃素對doxorubicin的抗癌效果具有協同作用。
並列摘要
Pegylated liposomal doxorubicin (PLD) was formulated by the polyethylene glycol-modified liposome that coated drug doxorubicin and often used on breast and ovarian cancer. PLD could reduce the cardiac toxicity, increase half-life and target to tumor tissue versus to traditional doxorubicin. But easily induced hand-foot syndrome (HFS) since prolonged circulation of PLD leading extravasation from microvascular to extremities and accumulate in those tissue and release doxorubicin. Doxorubicin produces reactive oxygen species that induced aberrant cell and progressively leading to cell apoptosis. Therefore, the aim of this study was to investigate whether antioxidants have abilities on reducing doxorubicin-induced ROS and synergistic anti-cancer effect with doxorubicin that could prevent hand-foot syndrome and enhance the efficacy of cancer treatment. In this study, we choose reseratrol, tetrahydroxystilbene glucoside, curcumin and extraction of antrodia cinnamomea as experimental subjects. The experiment divide into two parts: (1) 3T3 fibroblast cell was a normal cell model to evaluate to antioxidant ability of four antioxidants on preventing and reducing HFS. (2) The synergistic anti-cancer effect of antioxidants with doxorubicin on MCF-7 breast cancer model was evaluated. The results showed that pretreated resveratrol was the best antioxidant on protecting cell from ROS and curcumin was second one. If cotreated extraction of antrodia cinnamomea with doxorubicin could inhibit doxorubicin-induced ROS. Therefore, Resveratrol and curcumin increased cell antioxidant ability by improving activity of superoxide dismutase. Additionally, resveratrol and curcumin had synergistic effect with doxorubicin on MCF-7 breast cancer. According to these results, resveratrol and curcumin have potentials of being clinically applicable to prevent hand-foot syndrome and enhance the doxorubicin anti-cancer efficiency.