- 學位論文
(I) 正-乙基順丁烯二醯亞胺與砷於多聚ADP核糖化之交互作用 (II) 血漿中TGF-β1濃度改變量與攝護腺癌局部性冷凍治療的腫瘤控制成果之相關性研究
(I) Interplay between N-ethylmaleimide and arsenic on poly(ADP-ribosyl)ation (II) Association of change in plasma TGF-β1 levels with the oncological outcome of patients with localized prostate cancer treated with prostate cryoablation
摘要
(I)已知有數種器官，長期暴露於砷，會誘導腫瘤的生成與發展；然而，砷在氧化壓力媒介DNA（去氧核醣核酸）傷害的角色，仍未被透徹地瞭解。Poly(ADP-ribosyl)ation（多聚ADP核糖化），是一種細胞對DNA傷害的立即反應。多聚ADP核糖化能媒介DNA修補，並強化細胞存活能力。在此研究中，我們發現，將不同的人類癌細胞，暴露於三氧化二砷，會抑制過氧化氫誘導的多聚ADP核糖化。更有甚者，三氧化二砷會促進過氧化氫誘導的DNA傷害與細胞凋亡，導致細胞死亡增加。我們發現，正-乙基順丁烯二醯亞胺，為順丁烯二酸衍生之有機化合物，可逆轉三氧化二砷媒介之效應，強化多聚ADP核糖化，故減少細胞死亡並增加細胞存活。若以藥理學的方式，用丁硫氨酸-亞碸亞胺，抑制穀胱甘肽生成，會阻斷正-乙基順丁烯二醯亞胺對三氧化二砷之拮抗效應，延續三氧化二砷抑制多聚ADP核糖化，並導致DNA傷害。因此，本研究發現，正-乙基順丁烯二醯亞胺，為一具有潛力，以依賴穀胱甘肽的方式，對抗砷媒介的DNA傷害之解毒劑。 (II) 目的：評估細胞激素TGF-β1作為病人於冷凍治療後腫瘤控制結果之預測因子。 材料與方法：收集二零一一年十月，與二零一三年三月間，接受全腺體冷凍治療之攝護腺癌病人之手術前後之血液檢體。以磁珠免疫分析法，量化血漿TGF-β1濃度。手術前後TGF-β1改變量的定義為，術前至術後一至二個月之TGF-β1濃度差。生化性之復發係根據Phoenix criteria定義。以Mann–Whitney U，Kruskal–Wallis rank sum，以及Chi-square test比較次項目之臨床特徵，並應用Cox比例風險模型比較群組間之復發風險。 結果：總共包含75位攝護腺癌病人。在追蹤期中位數12個月（範圍：2.5–47個月）期間，11位病人有生化性復發，另外64位病人則無。我們觀察到，有生化性復發之病人，其手術前後TGF-β1濃度變化量，顯著地比無復發者大（中位數：470.3比78.9 pg/ml）（p < 0.05）。根據TGF-β1濃度變化量，病人被更進一步地以四分法分成四組，決定手術前後TGF-β1的濃度組別。第四組（≥430）預測到最差之生化性復發結果。 結論：手術前後血漿TGF-β1濃度，與局限性攝護腺癌冷凍治療後之生化性復發有關。術後血漿TGF-β1增加，可作為不良腫瘤控制結果，提示可能需要更積極追蹤或較早期之救援性治療之新預測因子。
並列摘要
(I) Long term exposure to arsenic has been known to induce neoplastic initiation and progression in several organs; however, the role of arsenic in oxidative stress-mediated DNA damage remains elusive. One of the immediate cellular responses to DNA damage is poly(ADP-ribosyl)ation (PARylation), which mediates DNA repair and enhances cell survival. In this study, we found that oxidative stress (H2O2)-induced PARylation was suppressed by arsenic (As2O3) exposure in different human cancer cells. Moreover, As2O3 treatment promoted H2O2-induced DNA damage and apoptosis, leading to increased cell death. We found that N-ethylmaleimide (NEM), an organic compound derived from maleic acid, can reverse As2O3-mediated effects, thus enhancing PARylation with attenuated cell death and increased cell survival. Pharmacologic inhibition of glutathione (GSH) with L-buthionine-sulfoximine blocked the antagonistic effect of NEM on As2O3, thereby continuing As2O3-mediated suppression of PARylation and causing DNA damage. Our findings identify NEM as a potential antidote against arsenic-mediated DNA damage in a GSH dependent manner. (II) Purpose: To evaluate the cytokine transforming growth factor beta 1 (TGF-β1) as a predictor of oncological outcomes in patients after cryoablation. Materials and Methods: Perioperative blood samples from prostate cancer (PC) patients who underwent total gland cryoablation between October 2011 and March 2013 were collected prospectively. Plasma TGF-β1 levels were quantified using magnetic bead immunoassay. The perioperative change in TGF-β1 was defined as the change in TGF-β1 from before surgery to 1–2 months after surgery. Biochemical recurrence (BCR) was defined according to the Phoenix criteria. The Mann–Whitney U, Kruskal–Wallis rank sum, and Chi-square test were used to compare the clinical characteristics of the subsets. The Cox proportional hazard model was applied for the comparison of recurrence risk among the groups. Results: A total of 75 PC patients were included. During a median follow-up period of 12 months (range: 2.5–47 months), 11 patients had BCR, and 64 patients did not. Significantly greater changes in the perioperative TGF-β1 levels (median: 470.3 vs. 78.9 pg/ml) were observed in patients with than without BCR (p < 0.05). According to the changes in TGF-β1 levels, the patients were further divided into 4 groups, which were determined in the quartile categories of perioperative TGF-β1 levels. Group 4 (≥430) predicted the worst BCR outcome. Conclusions: Perioperative plasma TGF-β1 levels were associated with BCR after prostate cryoablation for localized PC. Increase in postoperative plasma TGF-β1 may be a novel predictor for poor oncological outcomes and prompt a more aggressive follow-up or earlier salvage treatment.
並列關鍵字
PARP ； poly(ADP-ribosyl)ation ； N-ethylmaleimide ； arsenic ； DNA damage ； Prostate cancer ； Cryoablation ； TGF-b1 ； Prognostic factor ； Cancer progression參考文獻
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