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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 黃麗華(Lih-Hwa Hwang) | |
| dc.contributor.author | Suit-Fong Chan | en |
| dc.contributor.author | 陳雪芳 | zh_TW |
| dc.date.accessioned | 2021-06-13T02:01:20Z | - |
| dc.date.available | 2009-07-20 | |
| dc.date.copyright | 2007-07-20 | |
| dc.date.issued | 2007 | |
| dc.date.submitted | 2007-07-09 | |
| dc.identifier.citation | 1. Hoofnagle JH. Hepatocellular carcinoma: summary and recommendations. Gastroenterology 2004;127:S319-23.
2. Deuffic S, Poynard T, Buffat L, Valleron AJ. Trends in primary liver cancer. Lancet 1998;351:214-5. 3. Marrero JA. Hepatocellular carcinoma. Curr Opin Gastroenterol 2006;22:248-53. 4. Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 1999;353:1253-7. 5. Otto G, Heise M, Moench C, Herber S, Bittinger F, Schuchmann M, Hoppe-Lotichius M, Pitton M. Transarterial chemoembolization before liver transplantation in 60 patients with hepatocellular carcinoma. Transplant Proc 2007;39:537-9. 6. Battula N, Srinivasan P, Madanur M, Chava SP, Priest O, Rela M, Heaton N. Ruptured hepatocellular carcinoma following chemoembolization: a western experience. Hepatobiliary Pancreat Dis Int 2007;6:49-51. 7. Ruiz J, Mazzolini G, Sangro B, Qian C, Prieto J. Gene therapy of hepatocellular carcinoma. Dig Dis 2001;19:324-32. 8. Hwang LH. Gene therapy strategies for hepatocellular carcinoma. J Biomed Sci 2006;13:453-68. 9. Fillat C, Carrio M, Cascante A, Sangro B. Suicide gene therapy mediated by the Herpes Simplex virus thymidine kinase gene/Ganciclovir system: fifteen years of application. Curr Gene Ther 2003;3:13-26. 10. Kuriyama S, Mitoro A, Yamazaki M, Tsujinoue H, Nakatani T, Akahane T, Toyokawa Y, Kojima H, Okamoto S, Fukui H. Comparison of gene therapy with the herpes simplex virus thymidine kinase gene and the bacterial cytosine deaminase gene for the treatment of hepatocellular carcinoma. Scand J Gastroenterol 1999;34:1033-41. 11. Grimm CF, Ortmann D, Mohr L, Michalak S, Krohne TU, Meckel S, Eisele S, Encke J, Blum HE, Geissler M. Mouse alpha-fetoprotein-specific DNA-based immunotherapy of hepatocellular carcinoma leads to tumor regression in mice. Gastroenterology 2000;119:1104-12. 12. Kim TW, Hung CF, Kim JW, Juang J, Chen PJ, He L, Boyd DA, Wu TC. Vaccination with a DNA vaccine encoding herpes simplex virus type 1 VP22 linked to antigen generates long-term antigen-specific CD8-positive memory T cells and protective immunity. Hum Gene Ther 2004;15:167-77. 13. Cheng WF, Hung CF, Chai CY, Hsu KF, He L, Ling M, Wu TC. Tumor-specific immunity and antiangiogenesis generated by a DNA vaccine encoding calreticulin linked to a tumor antigen. J Clin Invest 2001;108:669-78. 14. Banchereau J, Palucka AK. Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol 2005;5:296-306. 15. Vollmer CM, Jr., Eilber FC, Butterfield LH, Ribas A, Dissette VB, Koh A, Montejo LD, Lee MC, Andrews KJ, McBride WH, Glaspy JA, Economou JS. Alpha-fetoprotein-specific genetic immunotherapy for hepatocellular carcinoma. Cancer Res 1999;59:3064-7. 16. Ribas A, Butterfield LH, Glaspy JA, Economou JS. Cancer immunotherapy using gene-modified dendritic cells. Curr Gene Ther 2002;2:57-78. 17. Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell 1992;71:1065-8. 18. Putzer BM, Stiewe T, Rodicker F, Schildgen O, Ruhm S, Dirsch O, Fiedler M, Damen U, Tennant B, Scherer C, Graham FL, Roggendorf M. Large nontransplanted hepatocellular carcinoma in woodchucks: treatment with adenovirus-mediated delivery of interleukin 12/B7.1 genes. J Natl Cancer Inst 2001;93:472-9. 19. Chang CJ, Chen YH, Huang KW, Cheng HW, Chan SF, Tai KF, Hwang LH. Combined GM-CSF and IL-12 gene therapy synergistically suppresses the growth of orthotopic liver tumors. Hepatology 2007;45:746-54. 20. Tazi A, Bouchonnet F, Grandsaigne M, Boumsell L, Hance AJ, Soler P. Evidence that granulocyte macrophage-colony-stimulating factor regulates the distribution and differentiated state of dendritic cells/Langerhans cells in human lung and lung cancers. J Clin Invest 1993;91:566-76. 21. Nastala CL, Edington HD, McKinney TG, Tahara H, Nalesnik MA, Brunda MJ, Gately MK, Wolf SF, Schreiber RD, Storkus WJ, et al. Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production. J Immunol 1994;153:1697-706. 22. Ohta T, Numata M, Yagishita H, Futagami F, Tsukioka Y, Kitagawa H, Kayahara M, Nagakawa T, Miyazaki I, Yamamoto M, Iseki S, Ohkuma S. Expression of 16 kDa proteolipid of vacuolar-type H(+)-ATPase in human pancreatic cancer. Br J Cancer 1996;73:1511-7. 23. Lu X, Qin W, Li J, Tan N, Pan D, Zhang H, Xie L, Yao G, Shu H, Yao M, Wan D, Gu J, Yang S. The growth and metastasis of human hepatocellular carcinoma xenografts are inhibited by small interfering RNA targeting to the subunit ATP6L of proton pump. Cancer Res 2005;65:6843-9. 24. Mitry RR, Sarraf CE, Havlik R, Habib NA. Detection of adenovirus and initiation of apoptosis in hepatocellular carcinoma cells after Ad-p53 treatment. Hepatology 2000;31:885-9. 25. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science 1991;253:49-53. 26. Bao JJ, Zhang WW, Kuo MT. Adenoviral delivery of recombinant DNA into transgenic mice bearing hepatocellular carcinomas. Hum Gene Ther 1996;7:355-65. 27. Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M, Ng L, Nye JA, Sampson-Johannes A, Fattaey A, McCormick F. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996;274:373-6. 28. Vollmer CM, Ribas A, Butterfield LH, Dissette VB, Andrews KJ, Eilber FC, Montejo LD, Chen AY, Hu B, Glaspy JA, McBride WH, Economou JS. p53 selective and nonselective replication of an E1B-deleted adenovirus in hepatocellular carcinoma. Cancer Res 1999;59:4369-74. 29. Milkiewicz M, Ispanovic E, Doyle JL, Haas TL. Regulators of angiogenesis and strategies for their therapeutic manipulation. Int J Biochem Cell Biol 2006;38:333-57. 30. Ribatti D, Vacca A, Dammacco F. The role of the vascular phase in solid tumor growth: a historical review. Neoplasia 1999;1:293-302. 31. Mignatti P, Rifkin DB. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 1993;73:161-95. 32. Aznavoorian S, Murphy AN, Stetler-Stevenson WG, Liotta LA. Molecular aspects of tumor cell invasion and metastasis. Cancer 1993;71:1368-83. 33. Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 1994;79:185-8. 34. Folkman J. Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 1972;175:409-16. 35. Ribatti D, Vacca A, Nico B, Sansonno D, Dammacco F. Angiogenesis and anti-angiogenesis in hepatocellular carcinoma. Cancer Treat Rev 2006;32:437-44. 36. Folkman J. Antiangiogenesis in cancer therapy--endostatin and its mechanisms of action. Exp Cell Res 2006;312:594-607. 37. Kerbel RS. A cancer therapy resistant to resistance. Nature 1997;390:335-6. 38. Kulke MH, Bergsland EK, Ryan DP, Enzinger PC, Lynch TJ, Zhu AX, Meyerhardt JA, Heymach JV, Fogler WE, Sidor C, Michelini A, Kinsella K, Venook AP, Fuchs CS. Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors. J Clin Oncol 2006;24:3555-61. 39. Kerbel RS, Yu J, Tran J, Man S, Viloria-Petit A, Klement G, Coomber BL, Rak J. Possible mechanisms of acquired resistance to anti-angiogenic drugs: implications for the use of combination therapy approaches. Cancer Metastasis Rev 2001;20:79-86. 40. Herbst RS, Sandler AB. Non-small cell lung cancer and antiangiogenic therapy: what can be expected of bevacizumab? Oncologist 2004;9 Suppl 1:19-26. 41. Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, Bouck NP. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 1999;285:245-8. 42. Tombran-Tink J, Shivaram SM, Chader GJ, Johnson LV, Bok D. Expression, secretion, and age-related downregulation of pigment epithelium-derived factor, a serpin with neurotrophic activity. J Neurosci 1995;15:4992-5003. 43. Becerra SP, Palmer I, Kumar A, Steele F, Shiloach J, Notario V, Chader GJ. Overexpression of fetal human pigment epithelium-derived factor in Escherichia coli. A functionally active neurotrophic factor. J Biol Chem 1993;268:23148-56. 44. Duh EJ, Yang HS, Suzuma I, Miyagi M, Youngman E, Mori K, Katai M, Yan L, Suzuma K, West K, Davarya S, Tong P, Gehlbach P, Pearlman J, Crabb JW, Aiello LP, Campochiaro PA, Zack DJ. Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced migration and growth. Invest Ophthalmol Vis Sci 2002;43:821-9. 45. Steele FR, Chader GJ, Johnson LV, Tombran-Tink J. Pigment epithelium-derived factor: neurotrophic activity and identification as a member of the serine protease inhibitor gene family. Proc Natl Acad Sci U S A 1993;90:1526-30. 46. Ek ET, Dass CR, Choong PF. PEDF: a potential molecular therapeutic target with multiple anti-cancer activities. Trends Mol Med 2006;12:497-502. 47. Abe R, Shimizu T, Yamagishi S, Shibaki A, Amano S, Inagaki Y, Watanabe H, Sugawara H, Nakamura H, Takeuchi M, Imaizumi T, Shimizu H. Overexpression of pigment epithelium-derived factor decreases angiogenesis and inhibits the growth of human malignant melanoma cells in vivo. Am J Pathol 2004;164:1225-32. 48. Takenaka K, Yamagishi S, Jinnouchi Y, Nakamura K, Matsui T, Imaizumi T. Pigment epithelium-derived factor (PEDF)-induced apoptosis and inhibition of vascular endothelial growth factor (VEGF) expression in MG63 human osteosarcoma cells. Life Sci 2005;77:3231-41. 49. Matsumoto K, Ishikawa H, Nishimura D, Hamasaki K, Nakao K, Eguchi K. Antiangiogenic property of pigment epithelium-derived factor in hepatocellular carcinoma. Hepatology 2004;40:252-9. 50. Filleur S, Volz K, Nelius T, Mirochnik Y, Huang H, Zaichuk TA, Aymerich MS, Becerra SP, Yap R, Veliceasa D, Shroff EH, Volpert OV. Two functional epitopes of pigment epithelial-derived factor block angiogenesis and induce differentiation in prostate cancer. Cancer Res 2005;65:5144-52. 51. Volpert OV, Zaichuk T, Zhou W, Reiher F, Ferguson TA, Stuart PM, Amin M, Bouck NP. Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor. Nat Med 2002;8:349-57. 52. Yamagishi S, Nakamura K, Ueda S, Kato S, Imaizumi T. Pigment epithelium-derived factor (PEDF) blocks angiotensin II signaling in endothelial cells via suppression of NADPH oxidase: a novel anti-oxidative mechanism of PEDF. Cell Tissue Res 2005;320:437-45. 53. Yamagishi S, Nakamura K, Matsui T, Inagaki Y, Takenaka K, Jinnouchi Y, Yoshida Y, Matsuura T, Narama I, Motomiya Y, Takeuchi M, Inoue H, Yoshimura A, Bucala R, Imaizumi T. Pigment epithelium-derived factor inhibits advanced glycation end product-induced retinal vascular hyperpermeability by blocking reactive oxygen species-mediated vascular endothelial growth factor expression. J Biol Chem 2006;281:20213-20. 54. O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997;88:277-85. 55. Oh SP, Warman ML, Seldin MF, Cheng SD, Knoll JH, Timmons S, Olsen BR. Cloning of cDNA and genomic DNA encoding human type XVIII collagen and localization of the alpha 1(XVIII) collagen gene to mouse chromosome 10 and human chromosome 21. Genomics 1994;19:494-9. 56. Felbor U, Dreier L, Bryant RA, Ploegh HL, Olsen BR, Mothes W. Secreted cathepsin L generates endostatin from collagen XVIII. Embo J 2000;19:1187-94. 57. Ferreras M, Felbor U, Lenhard T, Olsen BR, Delaisse J. Generation and degradation of human endostatin proteins by various proteinases. FEBS Lett 2000;486:247-51. 58. Hohenester E, Sasaki T, Olsen BR, Timpl R. Crystal structure of the angiogenesis inhibitor endostatin at 1.5 A resolution. Embo J 1998;17:1656-64. 59. Olsson AK, Johansson I, Akerud H, Einarsson B, Christofferson R, Sasaki T, Timpl R, Claesson-Welsh L. The minimal active domain of endostatin is a heparin-binding motif that mediates inhibition of tumor vascularization. Cancer Res 2004;64:9012-7. 60. Abdollahi A, Hlatky L, Huber PE. Endostatin: the logic of antiangiogenic therapy. Drug Resist Updat 2005;8:59-74. 61. Peroulis I, Jonas N, Saleh M. Antiangiogenic activity of endostatin inhibits C6 glioma growth. Int J Cancer 2002;97:839-45. 62. Holmgren L, O'Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995;1:149-53. 63. Wu Y, Yang L, Hu B, Liu JY, Su JM, Luo Y, Ding ZY, Niu T, Li Q, Xie XJ, Wen YJ, Tian L, Kan B, Mao YQ, Wei YQ. Synergistic anti-tumor effect of recombinant human endostatin adenovirus combined with gemcitabine. Anticancer Drugs 2005;16:551-7. 64. Luo X, Slater JM, Gridley DS. Enhancement of radiation effects by pXLG-mEndo in a lung carcinoma model. Int J Radiat Oncol Biol Phys 2005;63:553-64. 65. Tai KF, Chen PJ, Chen DS, Hwang LH. Concurrent delivery of GM-CSF and endostatin genes by a single adenoviral vector provides a synergistic effect on the treatment of orthotopic liver tumors. J Gene Med 2003;5:386-98. 66. Hajitou A, Grignet C, Devy L, Berndt S, Blacher S, Deroanne CF, Bajou K, Fong T, Chiang Y, Foidart JM, Noel A. The antitumoral effect of endostatin and angiostatin is associated with a down-regulation of vascular endothelial growth factor expression in tumor cells. Faseb J 2002;16:1802-4. 67. Kim YM, Jang JW, Lee OH, Yeon J, Choi EY, Kim KW, Lee ST, Kwon YG. Endostatin inhibits endothelial and tumor cellular invasion by blocking the activation and catalytic activity of matrix metalloproteinase. Cancer Res 2000;60:5410-3. 68. Shichiri M, Hirata Y. Antiangiogenesis signals by endostatin. Faseb J 2001;15:1044-53. 69. Abdollahi A, Hahnfeldt P, Maercker C, Grone HJ, Debus J, Ansorge W, Folkman J, Hlatky L, Huber PE. Endostatin's antiangiogenic signaling network. Mol Cell 2004;13:649-63. 70. Patek PQ, Collins JL, Cohn M. Transformed cell lines susceptible or resistant to in vivo surveillance against tumorigenesis. Nature 1978;276:510-1. 71. He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B. A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci U S A 1998;95:2509-14. 72. Lee YL, Ye YL, Yu CI, Wu YL, Lai YL, Ku PH, Hong RL, Chiang BL. Construction of single-chain interleukin-12 DNA plasmid to treat airway hyperresponsiveness in an animal model of asthma. Hum Gene Ther 2001;12:2065-79. 73. Passaniti A, Taylor RM, Pili R, Guo Y, Long PV, Haney JA, Pauly RR, Grant DS, Martin GR. A simple, quantitative method for assessing angiogenesis and antiangiogenic agents using reconstituted basement membrane, heparin, and fibroblast growth factor. Lab Invest 1992;67:519-28. 74. Jozkowicz A, Dulak J. Helper-dependent adenoviral vectors in experimental gene therapy. Acta Biochim Pol 2005;52:589-99. 75. Mori K, Duh E, Gehlbach P, Ando A, Takahashi K, Pearlman J, Mori K, Yang HS, Zack DJ, Ettyreddy D, Brough DE, Wei LL, Campochiaro PA. Pigment epithelium-derived factor inhibits retinal and choroidal neovascularization. J Cell Physiol 2001;188:253-63. 76. Graepler F, Verbeek B, Graeter T, Smirnow I, Kong HL, Schuppan D, Bauer M, Vonthein R, Gregor M, Lauer UM. Combined endostatin/sFlt-1 antiangiogenic gene therapy is highly effective in a rat model of HCC. Hepatology 2005;41:879-86. 77. Distler JH, Hirth A, Kurowska-Stolarska M, Gay RE, Gay S, Distler O. Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q J Nucl Med 2003;47:149-61. 78. Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 1991;64:327-36. 79. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983;219:983-5. 80. Calvo A, Feldman AL, Libutti SK, Green JE. Adenovirus-mediated endostatin delivery results in inhibition of mammary gland tumor growth in C3(1)/SV40 T-antigen transgenic mice. Cancer Res 2002;62:3934-8. 81. Zhang SX, Wang JJ, Gao G, Parke K, Ma JX. Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF-VEGF receptor 2 binding in diabetic retinopathy. J Mol Endocrinol 2006;37:1-12. 82. Voest EE, Kenyon BM, O'Reilly MS, Truitt G, D'Amato RJ, Folkman J. Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst 1995;87:581-6. 83. Duda DG, Sunamura M, Lozonschi L, Kodama T, Egawa S, Matsumoto G, Shimamura H, Shibuya K, Takeda K, Matsuno S. Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects of interleukin 12. Cancer Res 2000;60:1111-6. 84. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907-17. 85. Viloria-Petit AM, Kerbel RS. Acquired resistance to EGFR inhibitors: mechanisms and prevention strategies. Int J Radiat Oncol Biol Phys 2004;58:914-26. 86. Johnson BF, Clay TM, Hobeika AC, Lyerly HK, Morse MA. Vascular endothelial growth factor and immunosuppression in cancer: current knowledge and potential for new therapy. Expert Opin Biol Ther 2007;7:449-60. 87. Kanwar JR, Kanwar RK, Pandey S, Ching LM, Krissansen GW. Vascular attack by 5,6-dimethylxanthenone-4-acetic acid combined with B7.1 (CD80)-mediated immunotherapy overcomes immune resistance and leads to the eradication of large tumors and multiple tumor foci. Cancer Res 2001;61:1948-56. 88. Hsieh CL, Pang VF, Chen DS, Hwang LH. Regression of established mouse leukemia by GM-CSF-transduced tumor vaccine: implications for cytotoxic T lymphocyte responses and tumor burdens. Hum Gene Ther 1997;8:1843-54. 89. O'Reilly MS, Holmgren L, Chen C, Folkman J. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 1996;2:689-92. 90. Li B, Lalani AS, Harding TC, Luan B, Koprivnikar K, Huan Tu G, Prell R, VanRoey MJ, Simmons AD, Jooss K. Vascular endothelial growth factor blockade reduces intratumoral regulatory T cells and enhances the efficacy of a GM-CSF-secreting cancer immunotherapy. Clin Cancer Res 2006;12:6808-16. 91. Eggert AA, Schreurs MW, Boerman OC, Oyen WJ, de Boer AJ, Punt CJ, Figdor CG, Adema GJ. Biodistribution and vaccine efficiency of murine dendritic cells are dependent on the route of administration. Cancer Res 1999;59:3340-5. 92. Pan PY, Li Y, Li Q, Gu P, Martinet O, Thung S, Chen SH. In situ recruitment of antigen-presenting cells by intratumoral GM-CSF gene delivery. Cancer Immunol Immunother 2004;53:17-25. 93. Ren JG, Jie C, Talbot C. How PEDF prevents angiogenesis: a hypothesized pathway. Med Hypotheses 2005;64:74-8. 94. Bekeredjian R, Katus HA, Kuecherer HF. Therapeutic use of ultrasound targeted microbubble destruction: a review of non-cardiac applications. Ultraschall Med 2006;27:134-40. 95. Chen S, Ding JH, Bekeredjian R, Yang BZ, Shohet RV, Johnston SA, Hohmeier HE, Newgard CB, Grayburn PA. Efficient gene delivery to pancreatic islets with ultrasonic microbubble destruction technology. Proc Natl Acad Sci U S A 2006;103:8469-74. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/30331 | - |
| dc.description.abstract | 肝細胞癌通常有會較多血管異常增生的現象，所以很適合使用抗血管新生療法治療。然而，如果只使用單一種的抗血管新生因子對抗單一種的促血管新生因子，可能會因為腫瘤改合成另一種促血管新生因子而失效。尤以較後期的癌症，腫瘤會同時分泌多種的促血管新生因子以利於血管新生，所以在抗血管新生的策略中，最好同時能應用兩種或兩種以上的抗血管新生因子，比較能達到好的療效。
在這個研究中，我們嘗試使用Endostatin (ED)和Pigment Epithelium-Derived Factor (PEDF) 兩種抗血管新生因子治療原位性肝癌。我們應用了帶有小鼠Endostatin和人類PEDF的重組腺病毒載體。這些由重組腺病毒載體所表現的ED和PEDF在細胞內或動物體內都先經測試顯示具有生物活性。隨後我們同時打入帶有ED和帶有PEDF的重組腺病毒治療原位性肝細胞癌。動物實驗結果顯示，合併兩種不同的因子在治療腫瘤中達到加成性的效果。從組織免疫化學染色也發現，合併組相較於單一治療組可以加成性地降低腫瘤內的血管數目。抑制腫瘤的血管新生可以阻斷氧氣和養分，使腫瘤細胞凋亡。 接下來，我們也稍微觀察了兩種因子對於VEGF mRNA 表現的影響。不管是ED或PEDF都會使VEGF mRNA表現量降低；而合併治療組更放大了對於VEGF表現量的抑制。我們也意外的發現，合併治療組能誘導出比單一治療組更高量的腫瘤浸潤CD8+ T細胞。我們推論由於抗血管新生所導致的腫瘤細胞凋亡增加了腫瘤抗原的釋出，而誘導更高量的CD8+ T細胞。 | zh_TW |
| dc.description.abstract | The hepatocellular carcinoma is considered as one of the suitable targets for anti-angiogenic approaches due to its highly neovascularization. However, anti-angiogenic therapies aimed at single target can be neutralized by up-regulation of other pro-angiogenic factor. The fact that redundant angiogenic factor can be up-regulated by tumors in advanced stage of carcinoma suggests that the angiostatic strategies may require a combination of multiple anti-angiogenic factor.
In this study, we assessed the therapeutic effects of combination therapy with two anti-angiogenic factors, Endostatin (ED) and Pigment Epithelium-Derived Factor (PEDF), on established orthotopic liver tumor. We used recombinant adenoviral vector carrying genes encoded mouse ED or human PEDF. The adenovirally expressed endostatin and PEDF were biologically active, as demonstrated in vitro and in vivo. We performed an in situ tumor therapy with co-administration of ED and PEDF by recombinant adenoviral vectors. The results of animal experiments indicated that the combination of both factors provided a synergistic effect on tumor regression. The immunohistochemistry staining of endothelial cell marker in tumor regions also revealed that the combined therapy synergistically reduced the tumor vascularization. The inhibition of tumor vascularization which starved tumors from oxygen and nutrients induced apoptosis in tumor regions. Furthermore, we examined the impact of both factors on Vascular Endothelial Growth Factor (VEGF) mRNA level. A down-regulation of VEGF mRNA level was observed in response to ED or PEDF treatment. Moreover, the combined ED/PEDF treatment was able to augment the inhibition of VEGF expression. Surprisingly, the combination therapy also induced a higher level of tumor-infiltrating CD8+ T lymphocytes. We infer that the apoptosis induced by anti-angiogenesis gave rise to a bystander effect which activated higher levels of CD8+ T cells. Based on this hypothesis, we combined immunotherapy and anti-angiogenic therapy to improve the therapeutic effect on orthotopic hepatocellular carcinoma. We performed a combination of immunotherapy and anti-angiogenic therapy by adenoviruses-mediated gene transfer of ED, PEDF, IL-12, and GM-CSF simultaneously on the orthotopic hepatocellular carcinoma. The “four-in-one” therapy exhibited a synergistic effect on tumor regression compared to the immunotherapy group (GM-CSF + IL-12) or anti-angiogenic group (ED + PEDF) at the same dose. Our findings suggest that the co-action between two different treatment strategies can more effectively reduce tumor burden compared to single treatment strategy. Hence, the combination strategy between immunotherapy and anti-angiogenic therapy renders a promising treatment for hepatocellular carcinoma. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T02:01:20Z (GMT). No. of bitstreams: 1 ntu-96-R94445110-1.pdf: 2123020 bytes, checksum: 16bfcf3749cd414dcb508157560e008d (MD5) Previous issue date: 2007 | en |
| dc.description.tableofcontents | CHAPTER 1 INTRODUCTION 1
1. Hepatocellular Carcinoma 2 2. Gene therapy on hepatocellular carcinoma 3 Prodrug activation therapy by the transfer of suicide genes 3 2.2 Immun gene therapy 5 2.2.1 DNA vaccine 5 2.2.2 Dendritic cells 6 2.2.3 Co-stimulatory factors 7 2.2.4 Cytokines 7 2.3 Inhibition of oncogenes or the transduction of tumor suppressor genes 8 2.4 Oncolytic viruses 9 3. Anti-angiogenic therapy 10 3.1 Angiogenesis 10 3.2 Anti-angiogenic therapy 11 3.3 The advantages of anti-angiogenic therapy 12 3.4 The limitation of anti-angiogenesis 13 4. Pigment Epithelium-Derived Factor 14 4.1 The identification of PEDF 14 4.2 PEDF as angiogenic inhibitor 14 4.3 PEDF in anti-tumor studies 15 4.4 Mechanism studies of PEDF 16 5. Endostatin 17 5.1 The identification of Endostatin 17 5.2 Anti-tumor activity by ED 17 5.3 Mechanism studies of ED 18 6. Aim 19 CHAPTER 2 MATERIALS AND METHODS 20 1. Cell lines 21 2. HUVECs isolation and culture 21 3. Generation of recombinant adenoviral vectors 22 3.1 Plasmid constructions 22 3.2 Adenoviral vectors constructions 23 3.3 Generation of recombinant Adenoviruses 23 3.4 Titration of adenoviruses 24 4. Plasmid DNA purification 25 5. Western Blot analysis 26 6. In vitro functional assay of the anti-angiogenic factors 27 6.1 Proliferation inhibition assay 27 6.2 Transwell assay 28 7. In vivo functional assay of anti-angiogenic factors 29 8. Extraction of total RNA and synthesis of cDNA 30 9. Real-time PCR 31 10. Animal studies 33 10.1 Generation of orthotopic liver tumor 34 10.2 Tumor treatment and measurement 34 10.3 Electroporation 35 11. Immunohistochemistry staining 36 12. TUNEL assay 37 13. Statistical analysis 37 CHAPTER 3 RESULTS 39 1. Construction of recombinant adenoviral vector and expression of anti-angiogenic factors 40 2. In vitro biological activity assay of recombinant adenovirus-mediated ED and PEDF expressions 41 2.1 Proliferation inhibition assay 42 2.2 Transwell assay 43 3. In vivo biological assay recombinant adenovirus-mediated ED and PEDF expressions 43 4. Impact of ED and PEDF on angiogenic factors expression 44 5. Anti-angiogenic therapy on orthotpic hepatocellular carcinoma 47 5.1 Therapeutic effect 47 5.2 Reduction of tumor vascularization 48 5.3 Induction of apoptosis 48 5.4 The bystander effects 49 6. Survival curve of treatments with prolonged antiangiogenic genes delivery 50 7. Combination of antiangiogenic therapy with immunotherapy 51 7.1 Therapeutic effects 52 7.2 Reduction of tumor vascularization 53 7.3 Induction of apoptosis 54 7.4 The numbers of T cells induced in the therapy 55 CHAPTER 4 DISCUSSIONS 57 CHAPTER 5 PERSPECTIVES 64 1. The investigation of signaling pathways 65 2. The effects on lymphatic vessels 65 3. The activation status of tumor-infiltrating lymphocytes 66 4. Advances of alternate gene delivery system 66 CHAPTER 6 FIGURES 68 CHAPTER 7 SUPPLEMENTS 88 CHAPTER 8 REFFERENCES 94 LIST OF FIGURES Figure 1. Constructions of recombinant adenoviral vectors 69 Figure 2. The in vitro and in vivo expression of ED and PEDF 70 Figure 3. HUVECs proliferation inhibition assay 71 Figure 4. Transwell assay 72 Figure 5. Matrigel assay 73 Figure 6. Impact of ED and PEDF on angiogenic factors expression 74 Figure 7. Therapeutic effect of anti-angiogenic therapy 76 Figure 8. Reduction of tumor vascularization in anti-angiogenic therapy 77 Figure 9. Induction of apoptosis in anti-angiogenic therapy 78 Figure 10. The bystander effects 79 Figure 11. Treatments with prolonged anti-angiogenic genes delivery 81 Figure 12. Combined anti-angiogenic therapy with immunotherapy 82 Figure 13. Reduction of tumor vascularization in combined therapy 83 Figure 14. Induction of apoptosis in combined therapy 84 Figure 15. The immune response induced by combined therapy 85 LIST OF SUPPLEMENTS S1. PEDF sequence 89 S2. Transwell assay 90 S3. Anti-CD31 IHC staining of tumor regions in anti-angiogenic therapy 90 S4. TUNEL assay in anti-angiogenic therapy 91 S5. Anti-CD4 IHC staining of tumor regions in anti-angiogenic therapy 91 S6. Anti-CD8 IHC staining of tumor regions in anti-angiogenic therapy 92 S7. Anti-CD31 IHC staining of tumor regions in combined therapy 92 S8. TUNEL assay in combine therapy 93 S9. Anti-CD4 IHC staining of tumor regions in combined therapy 93 S10. Anti-CD8 IHC staining of tumor regions in combined therapy 94 | |
| dc.language.iso | en | |
| dc.subject | 原位性肝細胞癌 | zh_TW |
| dc.subject | 基因療法 | zh_TW |
| dc.subject | 抗血管新生 | zh_TW |
| dc.subject | Pigment Epithelium-Derived Factor | en |
| dc.subject | Endostatin | en |
| dc.subject | antiangiogenic gene therapy | en |
| dc.title | 合併Endostatin和PEDF抗血管新生因子應用於原位性肝細胞癌的基因療法 | zh_TW |
| dc.title | Antiangiogenic Gene Therapy on Orthotopic Hepatocellular Carcinoma Using Combination of Endostatin and Pigment Epithelium-Derived Factor | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 95-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳小梨(Show-Li Chen),賈景山(Jean-San Chia),王萬波(Won-Bo Wang) | |
| dc.subject.keyword | 抗血管新生,基因療法,原位性肝細胞癌, | zh_TW |
| dc.subject.keyword | antiangiogenic gene therapy,Endostatin,Pigment Epithelium-Derived Factor, | en |
| dc.relation.page | 104 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2007-07-09 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
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