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研究生:黃家鼎
研究生(外文):Chia-Ting Huang
論文名稱:利用腫瘤標的性胜肽作為台灣地區口腔癌治療之研究
論文名稱(外文):Identification of novel peptides targeting to oral squamous cell carcinoma in Taiwan
指導教授:郭彥彬郭彥彬引用關係
指導教授(外文):Mark Yen-Ping Kuo
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:口腔生物科學研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:英文
論文頁數:58
中文關鍵詞:噬菌體顯現法口腔癌胜肽
外文關鍵詞:phage displayoral cancerpeptide
相關次數:
  • 被引用被引用:1
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  • 收藏至我的研究室書目清單書目收藏:2
流行病學研究指出,台灣及東南亞地區的口腔癌發生大多與檳榔嚼食習慣有高度相關性。根據衛生署民國九十三年癌症登記報告指出,口腔癌在臺灣男性十大癌症中死亡率與發生率皆位居第四位。儘管近年在診斷及治療之科技上有不少進步,但整體來說,口腔癌病人之五年存活率並未有明顯改變。最近發現結合化學治療和放射線治療或可增加存活率。但這些治療方式無法選擇性對癌細胞做專一的治療,都有嚴重的副作用。專一性的標的療法或許可以解決此一問題。
先前研究指出,利用噬菌體顯現法技術可以篩選出與腫瘤細胞專一性結合的標的胜肽。本研究利用此方法對台灣口腔癌細胞株TW2.6進行篩選找出8種可以和TW2.6結合之噬菌體株。用此方法所找到噬菌體株,具有與口腔癌細胞及專一性結合的能力,同時也可以和在異體移殖的口腔癌腫瘤細胞有專一性的結合。 與口腔癌組織結合的能力分別高於普通組織約12.18到222.46倍。控制組的噬菌體株,則不具有與腫瘤組織專一性結合的能力。當我們將所篩選到的噬菌體株與其相對應的胜肽去做競爭性抑制,發現噬菌體株與口腔癌組織結合的能力可以被合成胜肽明顯抑制。些噬菌體株中以C39噬菌體與腫瘤組織專一性結合能力為最強,同時也能和台灣口腔上皮變異細胞株TW1.5做專一性結合。我們進一步將C39對應的胜肽連結微脂體包裹doxorubicin抗癌藥物(C39-peptide-Lipo-Dox)和單一只有此抗癌藥(Lipo-Dox)來進行抗癌療效比較。結果發現以C39-peptide-Lipo-Dox治療的SCID鼠效果最佳,腫瘤成長部分大小僅為原來的5.51倍。此外相較於Lipo-Dox治療的SCID鼠體重下降22.6%,C39-peptide-Lipo-Dox治療的SCID鼠體重沒有明顯的減少,顯示C39-peptide-Lipo-Dox藥物所引起的副作用受到良好的控制。因此C39標的胜肽不但能提高腫瘤治療效果及專一性,也能減輕藥物的毒性,可提供未來一個口腔癌新穎的治療方式。
In Taiwan, oral cancer is the fourth leading cause of cancer death in male. Approximately 80% of all oral cancer deaths are associated with the areca quid chewing habit. Despite significant improvements in diagnosis, local management, and chemotherapy of head and neck cancer, there is no significant increase in long-term survival rates over the past 30 years. To improve the survival rate, we identify several 12-mer peptides specifically binding to a Taiwanese oral squamous cell carcinoma (OSCC) TW2.6 with a phage displayed random peptide library. The selected phage clones and synthetic phage-derived peptides specifically bound to the cell surfaces of TW2.6 cells and a Taiwanese oral dysplasia cell line TW1.5, but not normal oral keratinocyes. In SCID mice bearing OSCC xenografts, the selected phage clones specifically bound to the tumor mass and the effects was inhibited by competition with phage-derived peptides. Among all the selected phage clones, C39-phage showed the highest targeting ability in tumor mass with 27.78-fold increase in concentration compared to control phage. Furthermore, C39-peptide-linked liposomes that carried doxorubicin (C39-peptide-Lipo-Dox) not only suppressed tumor growth better than Lipo-Dox but also showed no significant body weight change. These results indicate that the novel peptides specifically binding to OSCC cells and a good candidate for targeted drug delivery to OSCC solid tumors.
INDEX
Chapter 1 8
INTRODUCTION 8
Oral squamous cell carcinoma 8
The risk factors of oral cancer 9
Field cancerization 10
Molecular basis of HNSCC tumorgenesis 11
Origin of HNSCCs 13
Identified the different aetiologies and prognoses for HNSCCs 14
Chemoprevention for HNSCCs 15
Current treatment and new drugs development of HNSCC 16
Phage display 17
Chapter 2 18
MATERIALS AND METHODS 18
Cell lines and cell culture 18
Phage-display biopanning procedures 19
Idetification of phage clones by ELISA 19
DNA sequencing and computer analysis 20
Plaque assay 20
Peptide synthesis 21
Animal model for study of targeted oral therapy 21
Immunochistochemical staning of phage binding in xenograft tumor mass22
In vitro peptide competitive inhibition of TW2.6 cell-selected phage 23
Conjugation of peptides to PEG-DSPE 24
Preparation of Doxorubicin 24
Aminal model for targeting study 24
Cell viability (MTT) assay 25
Chapter 3 27
Chapter 4 40
RESULTS 40
Screening of oral cancer cell-binding phages and identification of their binding motif 40
Plaque assay of OSCC cell with different selected clones 41
Verification of the target binding activity of displayed peptides derived from selected phage clones 41
Animal model for targeting study of selected phages 42
Animal model for study of C39-peptide targeted therapy 43
Chapter 5 45
DISCUSSION 45
Chapter 6 51
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