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研究生:陳玉芳
研究生(外文):Yu-Fang Chen
論文名稱:[C-14]acetate於F98glioma之代謝特性探討:1-[14C]acetate與2-[14C]acetate之比較
論文名稱(外文):Characterizing Metabolic Fate of [C-14] acetate in F98 glioma cells: The Comparison of 1-[14C]acetate and 2-[14C]acetate
指導教授:王信二
指導教授(外文):Hsin-Ell Wang
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:放射醫學科學研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:51
中文關鍵詞:碳-11醋酸鹽碳-14醋酸鹽F98 Glioma腫瘤細胞積聚
外文關鍵詞:[11C]acetate[14C]acetateF98 Gliomametabolism
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醋酸鹽視同兩個碳之脂肪酸,可被生物細胞(包含腫瘤細胞)攝取利用,在細胞內進行分解代謝與合成代謝。腫瘤細胞因其異常增殖之特性或其他特殊機制,被預期比正常細胞有較高之醋酸鹽攝取量。以正子放射碳-11同位素標記之醋酸鹽([14C]acetate),在臨床上已被做為正子斷層掃描(positron emission tomography, PET)核醫藥劑。利用[14C]acetate進行全身非侵入性正子斷層掃描造影,除可用於某些惡性腫瘤之診斷和定位外,應用在心臟血流和心肌氧化代謝的評估上亦頗具成效。目前臨床PET造影最普遍使用的核醫藥物為氟-18標幟之去氧葡萄糖([F-18]fluorodeoxyglucose, [18F]FDG),然而[18F]FDG PET在腫瘤診斷有其應用上的限制,[11C]acetate可互補其不足,故未來在核醫藥物之領域,[14C]acetate仍有其難以替代之應用價值。
文獻報導,不同腫瘤對[11C]acetate之積聚模式有甚大差異,若能釐清[11C]acetate於不同腫瘤細胞之代謝機制,將更能提升其應用範圍,此外,將C-11標記於acetate的兩個不同碳原子(得到1-[11C]acetate與2-[11C]acetate)上,由於其代謝路徑的差異,亦會影響PET的造影結果評估。
本研究目的旨在探討腫瘤細胞對acetate之攝取代謝模式,以供臨床應用[11C]acetate於正子斷層掃描檢查之參考及依據。由於碳-11之半衰期甚短(僅20分鐘),本研究使用1-[14C]acetate與2-[14C]]acetate進行試驗(碳-14半衰期5730年),藉由分析腫瘤細胞和培養液中所生成含碳-14之代謝產物及其放射活度,並比較由1-[14C]acetate與2-[14C]acetate所得結果的差異,來瞭解腫瘤細胞對acetate之代謝機轉。
使用1-[14C]acetate與2-[14C]acetate分別進行F98 Glioma細胞體外攝取試驗,並收集實驗期間所釋出之二氧化碳。碳-14標記醋酸鹽及其放射性代謝產物,除phospholipid以薄層層析分析外,其餘主要藉高效液相層析儀及液態閃爍偵檢器,並與購得之碳-14標記標準品相比對,來進行含碳-14代謝產物之定性、定量分析。本研究發現,除[14C]CO2外,其他含碳-14之代謝產物至少有五類,包括檸檬酸循環之中間產物、glucose、amino acid、fatty acid與phospholipid。由培養液中的[14C]acetate濃度評估,腫瘤細胞對acetate代謝速率甚快,在試驗開始5分鐘內80%以上的[14C]acetate已被消耗;1-[14C]acetate與2-[14C]acetate代謝速率相似;在無葡萄糖與胺基酸供給之培養條件下,細胞對[14C]acetate之利用率達90%以上,且九成以上之代謝產物積蓄於細胞外液;1-[14C]acetate比2-[14C]acetate生成及排放[14C]CO2之速率較快;分析培養液與細胞內之lipid fraction、CO2 fraction及細胞內含碳-14代謝物的數量,顯示1-[14C]acetate與2-[14C]acetate呈現有意義之差異,故兩者雖有相同之生物特性,但不同位置碳-14之生化反應路徑並不相同。臨床上利用[11C]acetate做腫瘤造影診斷時,可依實際需要做最適之選擇。
Acetate can be utilized readily by living cells. It resembles the simplest fatty acid containing only two carbons and undergoes oxidation or anabolism by converting to acetyl-Co A in cytosol and mitochondria. The higher uptake of acetate in tumor than in normal tissues makes [11C]acetate a promising radiotracer for positron emission tomography (PET). [14C]acetate PET has been demonstrated useful for myocardial oxidative metabolism studies and for diagnosis of malignancy. Although [18F]FDG is now the most commonly used tracer for PET, [11C]acetate has shown more sensitive in a certain kinds of tumor than [18F]FDG. [11C]Acetate would be a tracer in complementary with, but not to replace the[18F]FDG in the clinical application.
The high fluctuation of [11C]acetate uptake in different kinds of tumors was found in clinical PET practice. The accumulation pattern of [11C]acetate in various tumor origins was not clear. It would be essential to clarify the metabolism of [11C]acetate which may help to account for the variations in tumor[11C]acetate uptake. This study aims to illuminate the metabolic fate of acetate that may characterize the accumulation patterns in malignant tumors, and to compare the metabolism of 1-[11C]acetate and 2-[11C]acetate for the optimization of clinical applications. Due to the short half life of C-11 (20 min), [14C]acetate (half life 5730 y) was use instead.
To determine the [14C]acetate metabolism, in vitro studies were performed with F98 glioma cell lines. The components of 14C-containing metabolites were identified with their authentic standards by high-performance liquid chromatography and thin-layer chromatography methods. The radioactivity in each fraction of extractives that contain 14C-incorporated metabolites was measured with liquid scintillation analyzer. All radiolabelled standards are purchased from commercial company.
The similar consumption rates of 1-[14C]acetate and 2-[14C]acetate in the incubation media indicate that the metabolic rate of the two compounds are almost the same. They showed the same biological characteristics in cellular uptake process. The metabolism of acetate was fast in the first 5 minutes. About 90% of [14C]acetate were metabolized by the glioma cells incubated in glucose and amino acid depleted medium within 30 min. The existence of 14C-containing CO2 and citrate verified that one of the metabolic pathways was via the TCA cycle. The production of CO2 from 1-[14C]acetate is more than that from 2-[14C]acetate demonstrated the fact that the first carbon atom in 1-[14C]acetate incorporated into CO2 earlier than the second carbon atom in 2-[14C]acetate. Most of the metabolites were retained in extracellular medium. The oxidation of acetate is fast in the beginning, then slow down after 30 minutes. The statistical comparison of 14C-containing lipid (P value: medium, 6.22E-07; cell:0.0003), CO2 (6027E-12) and metabolites in cell (6.01E-8) which were produced from 1-[14C]acetate and 2-[14C]acetate revealed significant difference. In conclusion, the environment and cell nutrition status will be the determinants of acetate metabolism. The kinetics of 1-[14C]acetate and 2-[14C]acetate have the same metabolism model. The C-14 in different position of acetate does undergo different catabolism or anabolism pathway.
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