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研究生:郭思堯
研究生(外文):Szu-Yao Kuo
論文名稱:利用活體噬菌體顯現法尋找口腔癌標的胜肽及發展標的治療之研究
論文名稱(外文):Identification of Oral Cancer-Targeted Peptides by in vivo Phage Display and Development of Ligand-Targeted Therapy for Oral Cacncer
指導教授:吳漢忠
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:2004
畢業學年度:92
語文別:中文
論文頁數:73
中文關鍵詞:口腔癌標的胜肽
外文關鍵詞:oral cancer-targeted peptide
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口腔癌在華人地區為一常見的癌症,且在台灣地區占男性癌症死亡率的第四位。一般來說,化學治療和放射線治療是主要治療癌症的方法之一,但是這些方法都有嚴重的副作用。由於這些治療方式無法選擇性對腫瘤細胞去做專一性的治療,導致正常細胞也遭受破壞。標的治療法不但能提高腫瘤治療的效果及專一性,也能減輕藥物的毒性,未來可提供一個新的口腔癌治療方式。
利用活體的噬菌體顯現法技術可以篩選出與腫瘤組織專一性結合的標的胜肽。在此研究中,我們已經利用活體噬菌體顯現法尋找出一些可以和口腔癌腫瘤組織結合之胜肽。運用此方法所找到數個噬菌體株,與口腔癌組織結合的能力分別高於普通組織約12到40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 (IVO-2 phage) 與其相對應的胜肽 (PIVO-2 peptide) 去做競爭性抑制實驗,可以看出IVO-2 噬菌體株與口腔癌組織結合的能力可以被合成胜肽PIVO-2明顯的抑制下來。為了證明這段專一性與腫瘤組織結合的胜肽,可以增進口腔癌的治療效果,以達到標的治療的目的,我們也將PIVO-2連結微脂體包�厤oxorubicin抗癌藥物 (LD-PIVO-2) 和單一只有此抗癌藥物 (LD) 來進行抗癌療效的比較。結果顯示,含有標的胜肽連結抗癌藥物LD-PIVO-2處理過後的老鼠,治療效果最佳 (存活率100%),口腔癌腫瘤明顯小於只有抗癌藥物 (LD) 處理後的老鼠 (存活率33.3%)。由此結果得知標的胜肽PIVO-2可以增進口腔癌的治療效果,並具有臨床發展標的治療的潛力。
另外,我們也將RGD 胜肽 (P1 peptide) 及angiostatin (Ag) 分別連結於抗癌藥物 (LD),並運用於癌症上的治療。在老鼠的實驗中,我們發現含有angiostatin或RGD胜肽的抗癌藥物除了療效極佳之外,也確實可降低藥物的毒性,減少藥物的副作用。因此,P1-LD 或Ag-LD可以提供作為口腔癌或其它癌症標的治療或抑制腫瘤血管新生治療的一種新穎的治療方向。
Oral cancer is a common cancer among Chinese living and ranks fourth in the mortality rate of male cancer patients in Taiwan. Cytotoxic chemotherapy or radiotherapy is major treatment as cancer therapies and is limited by serious side effects because therapies are not selective for malignant cells. Ligand-targeted therapy affords tumor specificity and limited toxicity and will promise new therapies to treat oral cancer.
In vivo phage display is a powerful tool for the discovery of ligands that selectively home to tumor. In this study, we used this method to identify specific peptides that could home to the Severe combined immunodeficiency (SCID) mice bearing oral cancer xenograft. Several phage clones selected in this manner homed to the oral cancer 12–40 times more than to control organs. Unselected control phage did not show this preference. Synthetic peptide PIVO-2, corresponded to IVO-2 phage displayed peptide sequence, was shown to inhibit the homing activity completely when co-injected into mice with the phage. To determine the efficacy of the tumor-homing peptide PIVO-2 for improvement the therapeutic index, systemic treatment of oral cancer bearing mice with doxorubicin-loaded liposome (LD) and peptide-conjugated LD (LD-PIVO-2) was performed. The mice showed significantly smaller tumor mass when we treated with the LD-PIVO-2 than LD only. LD-PIVO-2 treated mice have 100% survival rate but LD treated mice only have 33.3% survival rate. These results indicate that PIVO-2 peptide enhanced the efficacy of the drug against oral cancer xenografts in SCID mice and suggest that this peptide has a strong clinical potential for drug delivery guider to treat oral cancer.
We also developed ligand-targeted therapy using LD conjugated to angiostatin and RGD peptide. We found that the conjugation of LD with angiostatin or RGD peptide decrease the toxicity of cancer therapy to the tumor-bearing mice. This approach may provide a new strategy for the purpose of ligand-targeted therapy or anti-angiogenic therapy for solid tumors.
中文摘要..1
Abstract..3
Abbreviation..5
Introduction..8
Materials and methods..19
Results..24
Discussion..31
Figures..39
Reference..57
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