2015-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645805摘要：根據衛生福利部統計資料顯示，惡性腫瘤已連續32年蟬聯國人十大死因之首，平均每12分鐘就有一人死於癌症。如何透過最新、最進步的醫療技術改早期發現初期癌症，促進病人健康是每一位醫療人員的任務。癌細胞的特性是不斷地分裂生長，為了獲取生長所需的養分，癌細胞會改變其新陳代謝的方式(Warburg effect)，此代謝方式正是分子影像學偵測癌細胞設計的原理。有鑑於臨床上使用最廣泛的正子掃描放射製劑， 18F-fluorodeoxyglucose(FDG)， 有諸多因素如炎症病變等會影響腫瘤組織對於FDG之攝取，由而影響其臨床診斷之準確性。因此，本計畫希望藉由癌症利用glutamine的特殊代謝方式，設計一種正子掃描製劑來解決這個困擾。2011 年德國Koglin et al.發表了可評估腫瘤system xc- transporter(xCT)之活性的放射製劑(4S)-4-(3-18F-fluoropropyl)-l-glutamate 谷氨酸 (FSPG)，glutamate 的類似物。Cystine 及glutamate 透過細胞膜上的xCT 交換或進入細胞內，讓cystine 轉換成cysteine，進行glutathionebiosynthesis、抗氧化反應或進入truncated TCA cycle。正常組織除了腦、胰、脾及胸腺外，xCT的表現都很低，然而當細胞受到oxidative stress 後，xCT 的表現會大幅增加。動物及初步臨床前試驗顯示FSPG 在癌症組織呈現高對比，而發炎組織的攝取則極低，鑑別癌病變的能力優於FDG。本計畫構想上略分為三年來進行。第一年度開始於本院迴旋加速器中心進行FSPG 合成與標記，並同時進行品管測試及改進放射化學產率。第二至三年度開始，在經衛生福利部食品藥物管理署允許後，我們將計劃納入120 位臨床證實有肺癌、乳癌、肝胰惡性腫瘤病患在術前進行FSPG 與FDG 正子掃描。目的在比較在不同腫瘤對於同位素藥物之攝取有無差異，其診斷敏感度、特異性與準確度。以切下來的組織標本做anti-xC- antibody 及CD44 的免疫螢光染色看染色程度是否與FSPG uptake 成正比。之後將進行療效評估和復發追蹤的研究，比較FSPG 與FDG 掃描何者更能精準預估療效、預測腫瘤復發率和病患存活預後。本計畫FSPG 合成工作可由本院正子中心完成;但FSPG 製作成本相當昂貴，因此本研究計畫需獲得經費上的贊助才能夠實行--成功開發全新的高特異性及高敏感性偵測腫瘤PET 放射藥劑。矣獲得初步研究成果後，再進一步推廣用於國人常見及特有的癌症檢查，以造福更多病患。<br> Abstract: Cancer mortality has ranked the first in the cause of mortality in Taiwan for 32 years. The glucoseanalogue, 2-deoxy-[18F]fluorodeoxyglucose (FDG), is routinely used in positron emission tomography (PET).However, many tumors show low glycolytic activities, uptake not exceeding physiologic background or highactivity in inflammatory tissues mimicking malignancy. To overcome these limitations, suitable PET tracersother than FDG targeting tumor metabolism beyond enhanced glycolysis need to be exploited.Cancer showed not only increased glucose utilization but also increased uptake and turnover of aminoacids such as glutamine and glutamate. The high rate of glucose and glutamine influx results in an increase ofoxidative intermediates, an altered redox potential, and excessive reactive oxygen specifies. Glutathione andL-cysteine are needed in the antioxidant process, their continuous supplies are critical for cell survival andtumor growth. L-cystine in the blood is taken into the cell via a system Xc- transporter (xCT). Intracellularly,L-cystine can then be converted to L-cysteine which is used for glutathione synthesis. The xCT normallyshows low basal expression in normal tissues, but is upregulated during oxidative stress. Cancer cells showsurvival advantage over normal cells by higher expression of xCT, thus helping maintain a higher level ofglutathione to detoxify the reactive nitrogen or oxygen species generated during the metabolic activity ofcells. A new PET tracer targeting xCT activity, (4S)-4-(3-[18F]fluoropropyl-)-L-glutamate (FSPG), wasdeveloped by Koglin et al in 2011. Preclinical tumor models and pilot clinical studies showed excellenttumor visualization and high tumor to background ratios, low uptake in normal tissues, and did notaccumulate in inflammatory tissues as in FDG.This is a 3-year project. In the first year, we will optimize the labeling procedures, radiochemical yield,and quality of FSPG in our PET center. In the second and third years, after the approval of clinical trial byTFDA, clinical trials of FSPG will be performed in patients with lung, breast, HCC, and pancreatic cancers(n=120). FDG and FSPG PET will be performed for each patient before surgery for direct comparison intumor detection; correlate the radiological parameters with histology, immunohistochemistry of xCT andCD44 expression, and urinary biomarker of oxidative stress. Based on this study, the strength and limitationsof FSPG will be evaluated. This study not only has high academic interests but may provide strongevidence-based supplement data for applying the clinical utilization of FSPG PET in Taiwan.18F-FSPG谷氨酸正子掃描惡性腫瘤system xC - transporter18F-FSPGPETglutamatesystem xC- transportermalignancy