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研究生:翁千惠
研究生(外文):Cian-Huei Wong
論文名稱:Tamoxifen對於抑制血小板凝集作用之機轉探討
論文名稱(外文):Mechanisms Involved in the Inhibition of platelet Activity by Tamoxifen
指導教授:許準榕
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:96
中文關鍵詞:血小板凝集作用
外文關鍵詞:Tamoxifenplateletactivity
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Tamoxifen是一種選擇性動情激素受體調節劑(selective estrogen receptor modulators, SERMs),其作用機轉為與動情激素受體結合,進而影響內生性動情激素作用,目前廣泛的使用於乳癌的預防與治療。臨床上發現使用tamoxifen治療後的乳癌病患,會有血栓風險增加的現象,然而tamoxifen在血小板上的藥理學功未明確,因此我們有意探討tamoxifen在血小板活化過程中,對訊息傳遞方面的影響。研究結果顯示,tamoxifen隨著濃度的增加 (3-50 ?嵱),能有效的抑制collagen (1 ?慊/ml)、U46619 (1 ?嵱)、Thrombin (?~?|?~???nU/ml)與AA (60 ?嵱)所引起的人類血小板凝集反應,尤以對collagen活化血小板具有顯著的抑制作用;此外tamoxifen (5和7 ?嵱)亦可顯著地抑制collagen (1 ?慊/ml)所以引起的細胞內鈣離子移動以及降低thromboxane A2 (TxA2)的生合成。由實驗結果可知,tamoxifen (5和7 ?嵱)會抑制phospholipase C??2 (PLC?n??2)的活性,進而降低47 kDa蛋白質的磷酸化和細胞內鈣離子的移動。再者,tamoxifen (5和7 ?嵱)亦可抑制由collagen (1 ?慊/ml)所引起的p38 MAPK及ERK1/2的磷酸化反應。由上述結果證實,tamoxifen抑制血小板活性的作用可能涉及下列路徑: tamoxifen可能會調控PLC??2-PKC-p38 MAPK-PLA2-TxA2路徑,此外也會降低ERKs磷酸化,而阻止鈣離子的流動,最後抑制血小板的活化。
Tamoxifen, a selective estrogen receptor modulator (SERM), can bind to estrogens receptor and inhibit activation of estrogen. It is widely used for the prevention and treatment of breast cancer. In clinical treatment using tamoxifen is associated with an increased risk of thrombosis. However, the pharmacological functions of tamoxifen on platelets were not yet understood, we intresting the effect of tamoxifen on signal transduction in human platelet activation. In the result, tamoxifen concentration-dependently (3-50 ?嵱) inhibited human platelets aggregation stimulated by collagen (1 ?慊/ml), U46619 (1 ?嵱) and Thrombin (0.02 U/ml), especially by collagen. In addition, tamoxifen (5 and 7 ?嵱) also significantly inhibited intracellular Ca2+ mobilization and thromboxane A2 formation stimulated by collagen in human platelets. In this study, we suggest that the mechanisms of tamoxifen may be involved in inhibition of phospholipase C??2 (PLC?n??2) activity, followed by the 47 kDa protein phosphorylation and intracellular calcium mobilization. In addition, tamoxifen (5 and 7 ?嵱) reduced the phosphorylation of p38 MAPK and ERK1/2 stimulated by collagen (1 ?慊/ml) in human platelets. Furthermore, tamoxifen induced phosphorylation of vasodilator-
stimulated phosphoprotein (VASP). In conclusion, our study suggested that the mechanisms of tamoxifen (5 and 7 ?嵱) in anti-platelet activity maybe involved in the following: (1) tamoxifen regulated the activity of PLC??2-PKC-p38 MAPK-TxA2 pathway; Tamoxifen also decresed phosphorylation of ERKs, and then interfered intracellular calcium mobilization, finally inhibited platelet aggregation.
中文摘要………………………………………….1
英文摘要………………………………………….4
縮寫表…………………………………………….7
一. 緒論………………………………………..11
1-1研究背景…………………………………12
1-2研究動機及目的……………………………..26
1-3研究範圍……………………………………..27
二. 實驗材料與方法……………………………28
2-1實驗材料…………………………………….29
2-2實驗方法…………………………………….34
三. 結果……………………………………….46
四. 討論…………………………………………56
五. 結論………………………………………....63
表…………………………………………….......65
圖………………………………………………...68
參考文獻………………………………………...83
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