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研究生:張家哲
研究生(外文):Chia-Che Chang
論文名稱:分析雌性激素醌類代謝物紅血球蛋白胼合物於五年存活且未復發之乳癌病人
論文名稱(外文):Profiling of Hemoglobin Adducts of Estrogens Quinones in 5-year Survivors of Breast Cancer without Recurrence
指導教授:林伯雄林伯雄引用關係
指導教授(外文):Po-Hsiung Lin
口試委員:林喆李崇垓
口試委員(外文):Che Lin
口試日期:2017-07-10
學位類別:碩士
校院名稱:國立中興大學
系所名稱:環境工程學系所
學門:工程學門
學類:環境工程學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:65
中文關鍵詞:蛋白質胼合物乳癌血紅蛋白生物標記
外文關鍵詞:Protein adductBreast cancerHemoglobinBiomarker
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本研究的目的是同步分析雌性激素醌類與人類血紅蛋白(Hb)蛋白質胼合物,包括17β-雌二醇-2,3-醌(E2-2,3-Q)和17β-雌二醇-3,4-醌(E2- 3,4-Q),在中衍生自台灣地區5年無復發(5年存活者)的乳癌病人。我們分析了E2-3,4-Q和E2-2,3-Q的血紅蛋白質胼合物作為生物指標,用於評估雌性激素對醌類代謝物的配置,並將雌性激素醌類代謝物水平與治療前病人的水平進行比較。研究結果證實,5年存活者之血紅蛋白質樣本均檢測到E2-2,3-Q和E2-3,4-Q衍生的胼合物,包括E2-2,3-Q-4-S-Hb和E2-3,4-Q-2-S-Hb。 E2-2,3-Q衍生胼合物的水平與E2-3,4-Q衍生胼合物的無顯著正相關(相關係數r = 0.329,p<0.066)。 E2-2,3-Q-4-S-Hb及E2-3,4-Q-2-S-Hb的平均含量分別為217和368(pmole/g)。與乳癌病人相比,乳癌5年存活者的雌性激素醌類代謝物 (E2-2,3-Q-4-S-Hb 和 E2-3,4-Q-2-S-Hb總和)平均值相較於診斷/術前病人 (p<0.001)降低了60%。
進一步研究也發現,雌激素醌的累積量是乳腺癌產生的風險和乳腺癌復發風險為重要指標。此一研究結果證實,乳癌治療相關效應包括荷爾蒙治療(aromatase inhibitor 及tamoxifen)和環境因素的組合,包括生活方式和飲食中的變化,可以調節雌激素體內的代謝平衡,並將減少乳癌存活者中雌激素活性醌類代謝物的產生,降低復發的可能。
The aim of this study was to simultaneously analyze estrogen quinone-derived adducts profile, including 17β-estradiol-2,3-quinone (E2-2,3-Q) and 17β-estradiol-3,4-quinone (E2-3,4-Q), in human hemoglobin (Hb) derived from breast cancer patients with five year postoperative treatment without recurrence (5-year survivors) in Taiwan. Blood samples derived from breast cancer 5-year survivors without recurrence were collected. We analyzed the hemoglobin adducts of E2-3,4-Q and E2-2,3-Q as biomarkers for evaluation of disposition of estrogen to quinones and compared the estrogen quinone levels with those in patients before treatment. Our result confirmed that both E2-2,3-Q- and E2-3,4-Q-derived adducts, including E2-2,3-Q-4-S-Hb, and E2-3,4-Q-2-S-Hb, were detected in all 5-year survivors. Levels of E2-2,3-Q-derived adducts did not correlated significantly with those of E2-3,4-Q-derived adducts (correlation coefficient r = 0.329, p<0.066). Mean levels of E2-2,3-Q-4-S-Hb, and E2-3,4-Q-2-S-Hb were at 217 and 368 (pmole/g), respectively. This translated to 60-70% reduction in mean values of estrogen quinone-derived adducts (E2-2,3-Q plus E2-3,4-Q) in breast cancer 5-year survivors compared to those in the breast cancer patients with less than one year of diagnosis/preoperative treatment (BCP) (p<0.001). Our findings add support to the theme that cumulative body burden of estrogen quinones is an important indicator of breast cancer risk and breast cancer recurrence risk. We hypothesize that combination of treatment-related effects and environmental factors, including changes in life style and diet, may modulate estrogen homeostasis and diminish the production of estrogen quinones in breast cancer 5-year survivors.
摘要 i
Abstract ii
縮寫表 iii
縮寫表(續) iv
目錄 v
表目錄 viii
圖目錄 ix
第一章 前言 1
1.1 研究緣起 1
1.2 研究目的 1
第二章 文獻回顧 2
2.1 乳癌 2
2.1.1 乳癌的高危險群與預防 3
2.2 乳癌風險因子 4
2.2.1 年齡及身體質量指數 (Age and Body Mass Index) 4
2.2.2 種族 (Race) 5
2.2.3 家族病史 (Family History) 5
2.2.5 環境荷爾蒙 6
2.3 雌性激素 (Estrogen) 8
2.3.1 雌性激素的分類 8
2.3.2 雌性激素代謝因子 9
2.3.3 雌性激素的代謝機制 12
2.4 雌性激素與乳癌關聯性 14
2.5 蛋白質胼合物 (Protein adducts) 19
2.5.1 生物指標 (Biomarkers) 21
2.5.2 利用蛋白質胼合物作為生物指標 23
2.5.3 血紅蛋白 25
2.6 癌症診斷與治療之藥物 27
2.6.1 乳癌化學治療 28
2.6.2 乳癌荷爾蒙治療藥物-Tamoxifen 28
2.6.3 乳癌荷爾蒙治療藥物-芳香環轉化酵素抑制劑 29
第三章 實驗設計架構與假設 31
3.1 血紅蛋白胼合物之實驗設計架構 31
3.2 實驗研究假設 32
第四章 實驗材料與方法 33
4.1 實驗材料 33
4.1.1 化學藥品及號耗材 33
4.1.2 實驗設備 34
4.2 實驗方法 34
4.2.1 利用17β-Estradiol-2, 4, 16, 16, 17-d5製備雌性激素同位素蛋白質胼合物內標準品 35
4.2.2 TFAA derivatization分析方法 38
4.3 氣相層析質譜儀分析條件 38
4.4 血液血紅蛋白之透析 39
4.5 利用有機溶劑提純血紅蛋白 41
4.6 數據來源 41
第五章 實驗結果 43
5.1 雌性激素血紅蛋白質胼合物定性定量分析 43
第六章 討論 48
6.1 乳癌存活者之雌性激素受體(ER)、黃體激素受體(PR)、人類表皮生長因子受體(Her2)陽性、陰性之背景值探討 48
6.1.1 乳癌存活者之雌性激素受體(ER)陽性、陰性背景值 48
6.1.2 乳癌存活者之黃體激素受體(PR)陽性、陰性背景值 49
6.1.3 乳癌存活者之人類表皮生長因子受體(Her2)陽性、陰性背景值 50
6.2 彰化基督教醫院血液樣本中血紅蛋白質胼合物之相關性 51
6.3 彰化基督教醫院乳癌存活者、乳癌病人及健康對照組體內雌性激素醌類血紅蛋白質胼合物 53
第七章 結論與建議 56
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