跳到主要內容

臺灣博碩士論文加值系統

(44.192.22.242) 您好!臺灣時間:2021/08/01 11:42
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:林邁
研究生(外文):Mai Lin
論文名稱:FUdR、FDG、FET與FIAU作為追蹤腫瘤HSV-1-tk自殺式基因治療成效之評估研究
論文名稱(外文):Comparison of non-invasive in vivo imaging with radiolabeled FUdR, FDG, FET and FIAU for monitoring the tumor responses of suicide gene therapy using herpes simplex virus type 1 thymidine kinase and ganciclovir
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:63
中文關鍵詞:自殺式基因治療細胞攝取實驗生物分佈試驗正子造影
外文關鍵詞:suicide gene therapycellular uptakebiodistribution studyPET imahing
相關次數:
  • 被引用被引用:0
  • 點閱點閱:173
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
目的:以非侵入性造影方式評估治療成效對腫瘤的基因治療及其他療法極為重要。本研究的主要目為比較[18F]FUdR、[18F]FDG、L-[18F]FET與[123I]FIAU等不同類型之核醫造影劑,何者用於評估腫瘤的基因治療成果最為適當,並以荷有不同HSV-1-tk基因表現比例之腫瘤的小鼠為本研究的實驗動物模式。
研究方法:在FVB/N雌性小鼠肩膀與左右大腿,以皮下注射的方式分別注射含有1X105 NG4TL4、NG4TL4-STK及此二種細胞株之細胞混合液。十天後開始每日注射ganciclovir (10 mg/Kg)以進行HSV-1-tk自殺基因療法,連續七天,而在第0、4及7天分別利用[18F]FUdR、[18F]FDG、L-[18F]FET和[123I]FIAU等核醫藥物進行實驗動物的生物分布試驗與microPET/SPECT造影,以評估腫瘤療效和HSV-1-tk基因在小鼠體內的表現。
結果與討論:以ganciclovir治療前(第0天),混有不同HSV-1-tk基因表現比例之腫瘤大小無明顯差異,顯示NG4TL4與NG4TL4-STK細胞株在小鼠體內生長的速率相似。四類核醫藥物中,只有[123I]FIAU在腫瘤的積聚與HSV-1-tk基因表現程度呈高度線性相關。以ganciclovir治療四天後,[123I]FIAU在由NG4TL4-STK細胞所長成腫瘤的積聚量,大幅減少至僅稍高於背景值。比較治療期間腫瘤負荷與腫瘤對四類核醫藥物的積聚結果,顯示[18F]FUdR在腫瘤的積聚量與腫瘤增生速率高度相關,而[123I]FIAU則無此現象。此外,[18F]FDG與L-[18F]FET於ganciclovir治療前後在各腫瘤的積聚量並無明顯差異。
結論:綜合生物分布、microPET/SPECT影像與腫瘤負荷測量結果,顯示與核酸代謝機制相關的[18F]FUdR,由於能清楚反應腫瘤增生狀態,故在此四類核醫藥物中最具有及時監測腫瘤治療成效的潛力。
Objectives: The ability to monitor the tumor response non-invasively and continuously during gene therapy or other therapeutic strategies is quite important. This study aims to compare [18F]FUdR, [18F]FDG, L-[18F]FET and [123I]FIAU as microPET/SPECT imaging probes to monitor the tumor responses during HSV-1-tk suicide gene therapy with ganciclovir. The mice bearing four sarcomas in which each exhibit various HSV-1-tk gene expression were used as the animal model.
Methods: In the flanks of FVB/N female mice, four tumors per animal were grown by s.c. injection of the cell suspensions of either 1×105 of NG4TL4, NG4TL4-STK, or mixtures of these cell lines. 10 days after tumor cell inoculation, HSV-1-tk suicide gene therapy was started with daily consecutive i.p. injection of ganciclovir (10mg/kg). From the results of biodistribution studies and microPET/SPECT imaging, the relationships among tumor burden, radiodrugs ([18F]FUdR, [18F]FDG, L-[18F]FET and [123I]FIAU) accumulation and HSV-1-tk expression in tumors were investigated.
Results: Before ganciclovir treatment, no significant differences in weight and size of each tumor that exhibit different HSV-1-tk gene expression, suggesting similar in-vivo proliferation rates for NG4TL4 and NG4TL4-STK cells. The accumulation of radioactivity in the tumor at 24 h post [123I]FIAU injection correlated well with the fraction of NG4TL4-STK cells that inoculated to grow the tumor. After 4-day’s consecutive ganciclovir treatment, the accumulation of radioactivity in the tumor that grew from NG4TL4-STK cells at 24 h post [123I]FIAU injection was significantly reduced. Compared with the tumor burden, the accumulation of radioactivity in the tumor post [18F]FUdR injection correlated well with the growth rates of the tumors, while the uptake of [123I]FIAU could not reflect this phenomenon. The accumulation of radioactivity in all tumors post [18F]FDG and L-[18F]FET infection was nearly unchanged throughout the therapeutic period. The microPET/SPECT imaging studies also confirm these findings.
Conclusions: Our study clearly demonstrated that [18F]FUdR is a promising radiotracer to evaluate the proliferation potential of tumor. Among the four kinds of radiodrugs, [18F]FUdR was the most appropriate one in monitoring the tumor responses during suicide gene therapy, and thus most suitable in predicting the prognosis.
1. Greco O, Dachs GU. Gene directed enzyme/prodrug therapy of cancer: historical appraisal and future prospectives. J. Cell Physiol. 2001; 2001: 22-36.
2. Balzarini J, Bohman C, de Clercq E. Differential mechanism of cytostatic effect of (E)-5-(2-bromovinyl)-2’-fluoro-2’-deoxy-1-β-D-arabinofuranosyl-5-iodo-uracil. J. Biol. Chem. 1993; 1993: 6332-6337.
3. Cheng YC, Grill SP, Dutschman GE, Nakayma K, Bastow KF. Metabolism of 9-(1,3-dihydroxy-2-propxymethyl)guanine, a new anti-herpes virus compound, in herpes simplex virus-infected cells. J. Biol.Chem. 1983; 1983: 12460-12464.
4. Culver KW, Ram Z, Wallbridge S, Ishii H, Oldfield EH, Blaese RM. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 1992; 1992:1550-1552.
5. Freeman SM, Abboud CN, Whartenby KA, Packman CH, Koeplin DS, Moolten FL, Abraham GN. The “bystander effect”: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res. 1993; 1993: 5274-5283.
6. Moolten FL. Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a perspective cancer control strategy. Cancer Res. 1986; 1986: 5276-5281.
7. van Dillen IJ, Mulder NH, Vaalburg W, de Vries EFJ, Hospers GAP. Influence of the bystander effect on HSV-tk/GCV gene therapy. A review, Curr. Gene Ther. 2002; 2002:307-322.
8. W.A. Weber, N. Avril, M. Schwaiger. Relevance of position emission tomography (PET) in oncology. Strahlenther Onkol. 1999; 175: 356-373.
9. D. Delbeke. Oncology applications of FDG PET imaging: brain tumors, colorectal cancer, lymphoma, and melanoma. J. Nucl. Med. 1999; 40: 591-603.
10. C.K. Hoh, M.A. Seltzer, J. Franklin, J.B. dekernion, M.E. Phelps, A. Belldegrun. Position emission tomography in urological oncology. J. Urol. 1998; 159: 347-356.
11. Aren van Waarde, David C.P. Cobben, Albert J.H. Suurmeijer, Bram Mass, Willem Vaalburg, Erik F.J. de Vries, Peter L. Jager, Harald J. Hoekstra, Philip H. Elsinga. Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model. J. Nucl. Med. 2004; 45: 695-700.
12. K.J. Isselbacher. Sugar and amino acid transport by cells in culture: differences between normal and malignant cells. N. Eng. J. Med. 1972; 286: 929-933.
13. K. Ishiwata, W Vaalburg, P.H. Elsinga, A.M. Paans, M.G. Woldring. Comparing of L-[1-11C]methionine and L-[methyl-11C]methionine for measuring in vivo protein synthesis rates with PET. J. Nucl. Med. 1988; 29: 1419-1427.
14. W.A. Weber, H.J. Wester, A.L. Grosu, M. Herz, B. Dzewas, H.J. Feldmann, M. Molls, G. Stocklin, M. Schwaiger. O-(2-[18F]fluoroethyl)-L-tyrosine and L-[methyl-11C]methionine uptake in brain tumors: initial results of a comparative study. Eur. J. Nucl. Med. 2000; 27: 542-549.
15. H.J. Wester, C. Dittmar. Synthesis and biological evaluation of O-(2-[18F]fluoroethyl)-L-tyrosine (FET): a potential PET tracer for amino acid transport [abstract]. J. Nucl. Med. 1997; 38: 175P.
16. H.J. Wester, M. Herz , W. Weber, P. Heiss, R. Senekowitsch-Schmidtke, M. Schwaiger, G. Stocklin. Synthesis and radiopharmacology of O-(2-[18F]fluoroethyl)-L-tyrosine for tumor imaging. J. Nucl. Med. 1999; 40: 205-212.
17. P. Heiss, S. Mayer, M. Herz, H.J. Wester, M. Schwaiger, R. Senekowitsch-Schmidtke. Investigation of transport mechanism and uptake kinetics of O-(2-[18F]fluoroethyl)-L-tyrosine in vitro and in vivo. J. Nucl. Med. 1999; 40: 1367-1373.
18. A.H. Kaim, B. Weber, M.O. Kurrer, G. Westera, A. Schweitzer, J. Gottschalk, G.K. von Schulthess, A. Buck. 18F-FDG and 18F-FET uptake in experimental soft tissue infection. Eur J. Nucl. Med. 2002; 29: 648-654.
19. Zheng-Gang Zhang, Andreass Harstrick, et. al. Mechanisms of resistance to fluoropyrimidines. Seminars in Oncology. 1992; 19(2), suppl (3): 4-9.
20. Kiyotaka Sato, Motonobu Kameyama, et. al. Metabolic changes of glioma following chemotherapy: an experimental study using four PET tracers. J. Neur Oncol. 1992; 14: 81-89.
21. Alauddin MM, Conti PS. Synthesis and preliminary evaluation of 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG): a new potential imaging agent for viral infection and gene therapy using PET. Nucl. Med. Biol. 1998; 1998: 175-180.
22. Alauddin MM, Conti PS, Mazza SM, Hamzeh FM, Lever JR. Synthesis of 9-[(3-[18F]-fluoro-1-butyl-2-propoxy)methyl]guanine ([18F]FHPG): a potential imaging agent of viral infection and gene therapy using PET. Nucl. Med. Biol. 1996; 1996: 787-792.
23. Balatoni J, Finn R, Tjuvajev JG, Larson S, Blasberg RG. Synthesis and quality assurance of radioiodinated 2’-fluoro-2’-deoxy-1-β-D-arabinofuranosyl-5-iodio-
uracil. J. Labelled Cmp. Radiopharm. 1997;1997: 103.
24. Namavari M, Barrio JR, Tokyokuni T, Gambhir SS, Cherry SR, Herschman HR, Phelps ME, Satyamurthy N. Synthesis of 8-[(18)F]fluoroguanine derivatives: in vivo probes for imaging gene expression with positron emission tomography. Nucl. Med. Biol. 2000; 2000: 157-162.
25. Tjuvajev JG, Avril N, Oku T, Sasajima T, Miyagawa T, Joshi R, Safer M, Beattie B, DiResta G, Daghighian F, Augensen F, Koutcher J, Zweit J, Humm J, Larson SM, Finn R, Blasberg R. Imaging herpes virus thymidine kinase gene transfer and expression by positron emission tomography. Cancer Res. 1998; 1998: 4333-4341.
26. Alauddin MM, Shahinian A, Gordon EM, Bading JR, Conti PS. Preclinical evaluation of the penciclovir analog 9-(4-[(18)F]fluoro-3-hydroxymethylbutyl)
guanine for in vivo measurement of suicide gene expression with PET. J. Nucl. Med. 2001; 2001: 1682-1690.
27. Jacobs A, Voges J, Reszka R, Lercher M, Gossman A, Kracht L, Kaestle C, Wagner R, Wienhard K, Heiss WD. Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas. Lancet 2001; 2001: 727-729.
28. Win-Ping Deng, Wen K. Yang, Wen-Fu Lai, Ren-Shyan Liu, Jeng-Jong Hwang, Den-Mei Yang, Ying-Kai Fu, Hsin-Ell Wang. Non-invasive in vivo imaging with radiolabelled FIAU for monitoring cancer gene therapy using herpes simplex virus type 1 thymidine kinase and ganciclovir. Eur. Nucl. Med. Mol. Imaging 2004; 31: 99-109.
29. Yoshinao Abe, Hiroshi Fukuda, et. al. Studies on 18F-labeled pyrimidines: tumor uptakes of 18F-5-fluorouracil, 18F-5-fluro-2’-deoxyuridine and 18F-5-fluorouridine in animals. Eur. J. Nucl Med. 1983; 8: 258-261.
30. C. Y. Shiue, Alfred P. Wolf, et. al. Syntheses of 5’-Deoxy-5-[18F] flourouridine and related compunds as probes for measuring tissue proliferation in vivo. J. Labelled cmp. Radiopharm. 1984; 21(9): 865-873.
31. Kiichi Ishiwata, Minoru Monma, et. al. Automated synthesis of 5-[18F]Fluoro-2’-Deoxyuridine. Appl. Radiat. Isot. 1987; 38(6): 467-473.
32. Erik F.J. de Varies, Ingrid J. van Dillen, Aren van Waarde, T.M. Willemsen, Willem Vaalburg, Nanno H. Mulder, Geke A.P. Hospers. Evaluation of [18F]FHPG as PET tracer for HSVtk gene expression. Nucl. Med. Biol. 2003; 30: 651-660.
33. Diane D. Ilsley, Suk-Hee Lee, et al. Acyclic Guanosine Analogs Inhibit DNA Polymerases □, □, and □ with Very Different Potencies and Have Unique Mechanisms of Action. Biochemistry 1995; 34: 2504-2510.
34. Johan F Vansteen kiste, Lymph node staging in NSCLC with FDG-PET scan:A prospectsive study on 690 Lymph node stations from 68 patients. J. Clin. Onco. 1998; 16 (6).
35. D. N. Abrams, E. E. Knaus, et. al. 18F-5-Fluoro-2’-deoxyuridine as a radiopharceutical for diagnostic oncology. The Chemistry of Radiopharmaceuticals. 1978.
36. D. N. Abrams, E. E. Knaus, et. al. Tumor Uptake of Radiolabeled Pyrimidine Bases and Pyrimidine Nucleosides in animal Models-II. 6-[3H]-5-Fluoro-2’-deoxyuridine. International Journal of Nuclear Medicine and Biology. 1979; 6: 103-107.
37. Donald W. Kufe, Peter Scott, et. al. Biologic Effect of 5-Fluoro-2’- deoxyuridine Incorporation in L1210 Deoxyribonuclleic Acid. Biochemical Pharmacology. 1983; 32(8): 1337-1340.
38. Jean-Pierre Sommadossi, Claude Aubert, et. al. Kinetics and metabolism of a new fluoropyrimidine, 2’-deoxy-5-fluorouridine, in humans. Cancer Research. 1983; 43: 930-933, Feb.
39. R. Nayak. Thymidine inhibits the incorporation of 5-fluoro-2’- deoxyuridine to DNA of mouse mammary tumor. Biochemical and Biophysical Research Communications. 1992; 184(1): 467-470.
40. DC. MacLaren, T. Toyokuni, SR.Cherry, JR. Barrio, ME. Phelps, HR. Herschman, and SS. Gambhir. PET imaging of transgene expression. Biological Psychiatry. 2000; 48(5), 337-48.
41. Juri G. Tjuvajev, Gunther Stockhmmer, et. al. Imaging the expression of transfected genes in vivo. Cancer Research, 1995; 55, 6126-6132.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關論文
 
1. 張鈿富(民89)。需求導向的教育經費改革趨勢。教育研究月刊,90期,頁72-80。
2. 張秀蓮(民89)。中央統籌分配稅制度之探討。主計月報,537期,頁39-49。
3. 朱澤民(民82)。我國政府基金分類問題之探討。財稅研究,25(4),頁162-169。
4. 張力人(民83)。談如何加強非營業循環基金之管理(上)-以國軍附設民眾診療作業基金為例。主計月報,77(4),頁22-25。
5. 宋棋超(民92)。地方教育預算之探究(上)。師說,170,頁48-51。
6. 宋棋超(民91)。「財政收支劃分法」修正草案之平議。財稅研究,34(5),頁31-53。
7. 莊振輝(民82)。我國預算法有關基金分類條文之研究(上)。今日會計,56期,頁25-53。
8. 許振明(民91)。財政收支劃分法之爭議。國家政策論壇,2(4),頁150-151。
9. 許添明(民89)。我國國教經費補助方式與需求本位補助公式。教育學刊,16期,頁139-162。
10. 陳金元(民91)。從稅收分配探討地方財政問題。財稅研究,34(6),頁138-154。
11. 陳美玲(民91)。財政收支劃分法修正案評析。中國稅務旬刊,1815期,頁14-15。
12. 陳麗珠(民90a)。國立大學校務基金政策實施成效之檢討。教育政策論壇。4(1),頁118-166。
13. 陳麗珠(民90b)。教育經費編列與管理法之評析。教育學刊。17期,頁125-145。
14. 陳麗珠(民91b)。地方補助款制度化政策對國民教育財政影響之研究。教育學刊。19期,頁91-119。
15. 陳麗珠(民91c)。國民教育經費基本需求之探討。教育學刊。18期,頁185-211。