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研究生:邱見怡
研究生(外文):Chien-Yi
論文名稱:探討鼻咽癌患者其血漿中基質金屬蛋白水解酶-2及 -9在同步放射化學治療前後之表現與臨床相關意義
論文名稱(外文):Study of plasma matrix metalloproteinase -2 and -9 level during concurrent chemoradiotherapy and clinicopathologic significance in patients with nasopharyngeal carcinoma
指導教授:劉文山劉文山引用關係楊順發
指導教授(外文):Wen-Shan LiuShun-Fa Yang
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:醫學研究所
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:2009
畢業學年度:97
語文別:中文
論文頁數:64
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鼻咽癌好發於中國南方和東南亞地區,台灣亦是好發區域之ㄧ,它主要的致病因子可分為基因敏感性、化學致癌物與EB病毒的感染等因子。鼻咽癌是屬於高輻射敏感性與化療敏感性的癌症,在癌症初期,放射治療乃是主要的治療方式。但是當癌症發展成具高侵襲性的晚期,同步放射化療就是主要的治療方式。雖然早期的鼻咽癌容易被控制或治癒,但是對於晚期的病人卻有高的復發率與遠端轉移的潛在性。基質金屬蛋白水解酶(matrix metalloproteinase)-2及-9乃是屬於MMP家族之ㄧ,主要在分解第四型的膠原蛋白乃是屬於細胞外基質的主要成分,這被認為是造成腫瘤侵襲與轉移的重要因子。近來研究顯示在細胞株中可以觀察到EB病毒上的潛伏膜蛋白-1會促使MMP -9的活性表現,該研究也提出這可能就是潛伏的膜蛋白-1藉由誘發MMP-9的活化,因而造成鼻咽腫瘤侵襲與轉移的機制。另外又有研究指出,在肺癌、乳癌與直腸癌病人經由放射線的治療會使MMP-2及-9的活性表現上升。而MMP-2及-9的大量表現已在許多的癌症組織中可以觀察到,甚至也可在病人的周邊血液中測得該蛋白酶的高濃度表現。本篇研究主要探討藉由鼻咽癌病人在同步放射化學治療期間血漿中MMP-2及-9的變化與臨床表現的相關性。本實驗病人血液的收集皆來自中山醫學大學附設醫院放射腫瘤科,具臨床病理切片確認為鼻咽癌患者,腫瘤分期乃是根據2002年AJCC公佈的分期標準,病人皆接受相同的同步放射化學療法。20位鼻咽癌患者的血液樣本收集共分四階段,每次抽5mL的樣本儲存於EDTA採血管中,然後再進行明膠蛋白酵素電泳法分析該蛋白酶活性表現與酵素免疫分析法分析濃度的變化。
結果顯示血漿MMP -2和-9的濃度表現和鼻咽癌病人的年齡、性別、腫瘤大小和淋巴結轉移並無明顯相關性。血液中的嗜中性白血球計數與血漿中MMP -9則有直接的相關性,具有統計學的意義。另外,在較具侵襲性的鼻咽癌患者中其血漿中MMP -9的濃度(mean= 68.6 ng/mL)明顯高於其他鼻咽癌患者(mean= 45.7 ng/mL),但是這現象在血漿MMP -2並無明顯相關。另一個值得探討的是血漿中MMP -9在治療前後的濃度變化,在具侵襲性的鼻咽癌患者在合併前導性化療與同步放射化療之後,血漿中MMP -9的濃度依然維持高濃度。但因為我們的樣本數量太少,導致我們的結果並無統計學上的意義。
總結以上,同步放射化學治療可以降低血漿中MMP -9的濃度,但是在較具侵襲性的鼻咽癌患者方面並無觀察到相同反應。因此,我們推論血漿中高濃度的MMP -9也許會促進癌細胞的擴散,進而造成腫瘤持續的侵犯、復發與遠端轉移。


Nasopharyngeal carcinoma (NPC) is an endemic tumor in southern China and Southeast Asia, as well as in Taiwan. The main etiologic factors include genetic susceptibility, chemical carcinogens and association with Epstein-Barr virus (EBV) infection. NPC is highly radiosensitive and chemosensitive. Presently, radiotherapy remains a common treatment for early disease, while concurrent chemoradiotherapy is being increasingly accepted as the standard treatment for advanced disease. Although NPC at early stages can be cured by radical radiotherapy, there is a high recurrence rate in patients with advanced NPC. NPC is a highly metastatic and invasive malignant tumor in which the EBV genes encoding LMP-1 is expressed. Latent membrane protein 1 (LMP1), an EBV membrane protein is considered to be the EBV oncoprotein. Matrix metalloproteinase (MMP) -2, -9 are the MMP families, degrade Type IV collagen, a major component of extracellular matrix and is believed to be crucial for cancer invasion and metastasis. Recently, the study has shown that LMP1 induces MMP-9 in vitro cell line, which suggests the possibility of a mechanism in which LMP1 of EBV contributes to the invasion and metastasis of NPC by the induction of MMP-9. Upregulation of MMP-2 and -9 expression is observed in many cancers and high level of these proteins are found in peripheral blood of many cancer patients and increased plasma level of MMP-9 has been found in lung and breast and rectal cancer post radiotherapy. In this study, we aimed at evaluating the plasma pro-MMP-2 and pro-MMP-9 pro-enzymes levels during the course of CCRT and their clinical significances in patients with nasopharyngeal carcinoma.
Patients with histological confirmed NPC attending the Department of Radiation Oncology at the Chung Chan Medical University Hospital. Cancer stage is according to 2002 AJCC staging system. All patients were treated with a concurrent chemoradiotherapy protocol. All patients were drawn 5mL of peripheral blood into an EDTA blood collection tubes with four times totally. The plasma pro-MMP2 and pro-MMP9 activity were measured in 20 NPC patients by gelatin zymography and the level were measured by enzyme linked immunosorbant assay (ELISA).
The study result showed the plasma MMP-2,-9 concentration were not correlated with sex, age, T stage, lymph node metastatsis. But the neutrophils count was positive correlation to the plasma MMP-9 concentration that were statistically significant. In addition, the plasma MMP-9 levels ( mean= 68.6 ng/ml ) in the advanced stage are higher than in early stage ( mean= 45.7 ng/ml ) patients, while no difference in plasma MMP-2 levels was found. Furthermore, the authors have also find the kinetic of plasma MMP-9 concentration during CCRT in Group 2. was different from Group 1. NPC patients. The plasma MMP-9 concentration was still at high level in Goup 2. patients post CCRT. Our results were not statistically significant, because the sample sizes were small.
Our conclusion, CCRT can be reduced effectively the plasma MMP-9 levels in early stage NPC. The more aggressive NPC patients still have high level of plasma MMP-9 post combine neo-adjuvant with CCRT. A high level of plasma MMP-9 may facilitate spreading of cancer cell and therefore a more aggressive tumor dissemination, recurrence and distant metastatsis.


中文摘要 Ⅰ
英文摘要 Ⅲ
縮 寫 Ⅵ
目 錄 Ⅶ
表目錄 Ⅸ
圖目錄 Ⅹ
壹. 文獻綜論 1
一. 鼻咽癌 1
1. 鼻咽癌的病原學 2
1.1. 鼻咽癌與EB病毒的關係 2
1.2. EB病毒的特性與在鼻咽癌發生過程中的角色 3
1.3. 潛伏性膜狀蛋白 4
2. 鼻咽癌的治療 6
2.1. 放射治療 6
2.1.1. 強度調控放射治療 7
2.1.2. 導航螺旋式光子刀 8
2.2. 同步放射化學療法 9
二. 基質金屬蛋白水解酶 10
三. 鼻咽癌與基質金屬蛋白水解酶的相關性 13
貳. 研究動機 15
參. 材料與方法 16
一. 研究對象選擇 16
1. 病理組織 16
2. 腫瘤分期系統 16
3. 放射治療 16
4. 化學療法 17
5. 治療反應與預後評估 17
二. 實驗方法 17
1. 血液樣本採集與處理 17
2. 基質金屬蛋白水解酶之活性分析 18
2.1. 明膠蛋白酵素電泳法 18
2.2. 酵素免疫分析法 19
三. 統計分析 24
肆. 結果 25
一. 臨床病人基本資料 25
二. 臨床生理數值 WBC count在治療前後的表現 27
三. MMP -9 治療前後的變化 27
四. MMP -2 治療前後的變化 28
五. MMP -9/ MMP -2 ratio的變化 29
六. MMP -9與臨床病理、治療反應的相關性 29
七. MMP -2與臨床病理、治療反應的相關性 29
八. MMP -9/ MMP -2 ratio與臨床病理、治療反應的相關性 30
九. MMP -9、MMP -2 和 MMP -9/ MMP -2 ratio與 白血球和嗜中性白血球的相關性 30
伍. 討論 31
一. 血漿 MMP -9、MMP -2與臨床病理的相關性 31
二. 血漿 MMP -9變化與臨床生化指標相關意義 31
三. 放射線治療可能引發血漿 MMP -9表現的分子機制 32
四. 高侵襲性鼻咽癌具有高度腫瘤持續發展或是遠端轉移潛在性 33
陸. 結論 35
柒. 未來展望 36
捌. 參考文獻 37
玖. 圖表與圖表說明 47
附錄 60


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