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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 吳漢忠(Han-Chung Wu) | |
dc.contributor.author | Cheng-Jou Yang | en |
dc.contributor.author | 楊振柔 | zh_TW |
dc.date.accessioned | 2021-06-08T01:47:33Z | - |
dc.date.copyright | 2016-08-26 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-08-05 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19173 | - |
dc.description.abstract | 根據美國癌症協會在2015年的統計上:共有231,840位女性罹患乳癌,目前已位居女性癌症之首,致死率更為女性癌症的第二名,研究資料上顯示好發於女性20~59歲。在臺灣衛生署2013年的統計,女性乳癌的死亡率也位居第四名。然而其中癌症表面第二型人類表皮生長因子(HER2) 扮演重要的角色。此因子是細胞膜上的一種酪胺酸激酶也是ERBB的家族成員之一。研究顯示有百分之二十的乳癌患者具有高度表現第二型人類表皮生長因子的情況發生,且當細胞的第二型人類表皮生長因子過度表達時會提高癌細胞增生及轉型的風險,進一步會造成較差的癒後效果。在現有的研究指出專一性抗體已被廣泛的應用於免疫學與免疫學分子診斷,可用來篩選病人是否適合針對第二型人類表皮生長因子做癌症標靶治療。
Trastuzumab而其藥品名為Herceptin,是一種人源化專一性對抗第二型人類表皮生長因子的單株抗體,目前已經被廣泛的應用於臨床醫學上。然而trastuzumab的治療在大部分的病人中容易產生抗藥性,因此期望能夠生產出新一代的抗體,發展出新的治療癌症方法。因此本篇研究利用融合瘤技術(hybridoma technology) 發展出新的抗第二型人類表皮生長因子單株抗體,且共83株,其中六株可用於西方墨點法;而另外三株可用於免疫組織染色法,這些在未來皆可對臨床診斷上有非常大的助益。另一方面也發現有其中的六株抗體能直接引起癌細胞凋亡,而在內吞作用上也同樣具有其成效,此研究成果証實這些新的第二型人類表皮生長因子抗體,可提供未來在治療高度表現第二型人類表皮生長因子的乳癌上一個癌症治療的新策略。 | zh_TW |
dc.description.abstract | According to the American Cancer Society, 231,840 women suffered from breast cancer, which has become the most prevalent cancer with second highest mortality rate among women in the U.S. in 2015. In the statistical analysis provided by the Department of Health in Taiwan, the mortality for breast cancer was ranked the fourth among the Taiwanese women in 2013. The previous studies indicated that human epidermal growth factor receptor 2 (HER2), a membrane tyrosine kinase and one of ERBB family members, plays a critical role in the development and progression of breast cancer. In addition, the over-expression of HER2 also can be observed in 20% of breast cancer patients. The overexpression of HER2 not only increases the risk for cell proliferation and cancer transformation, but it also contributes to poor prognosis after therapeutic operation. HER2 is therefore considered as an invaluable monitor to anti-tumor treatment research, especially for patient selection for targeted therapy. Trastuzumab (Herceptin), a specific HER2 humanized monoclonal antibody, is applied widely in the clinics for the treatment of breast cancer. The trastuzumab treatment; however, was evidenced as the drug resistance to the majority of patients. Therefore, the alternative antibodies will be generated in this project and expect to develop the new therapies. This study aims to investigate the therapeutic efficacy of specific anti-HER2 monoclonal antibodies (mAbs) generated using the hybridoma technology. The six anti-HER2 mAbs can be used in Western blot assay, while three anti-HER2 mAbs can be used in immunohistochemistry (IHC) for further clinical and molecular diagnosis. In addition, we founded that six anti-HER2 mAbs can induce apoptosis and lead to cancer cells death. Furthermore, we investigated the mechanism and function of endocytosis. In conclusion, the major goal of this study is to develop effective and specific anti-HER2 mAbs against HER2 positive breast cancer. Another objective is to understand the molecular functions of these anti-HER2 mAbs in apoptosis and endocytosis for further development into anti-cancer therapeutics and clinical molecular diagnostic reagents. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T01:47:33Z (GMT). No. of bitstreams: 1 ntu-105-R03444003-1.pdf: 3206237 bytes, checksum: df213c4b34820f0c6360d10e683c58a9 (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 致謝 I
Contents III Content of tables and figures VI List of abbreviations VII 中文摘要 IX Abstract X Chapter 1 Introduction 1 1.1 Epidemiology of breast cancer 1 1.2 Pathogenesis of breast cancer 2 1.3 Treatment of breast cancer 3 1.3.1 Surgical therapy 4 1.3.2 Radiotherapy 4 1.3.3 Hormonal therapy 5 1.3.4 Chemotherapy 5 1.3.5 Targeted therapy 6 1.4 Human Epidermal Growth Factor Receptor 2 (HER2) 6 1.5 Targeted therapy for HER2 8 1.5.1 Monoclonal antibodies 8 1.5.2 Antibody-drug conjugate 10 1.5.3 Tyrosine kinase inhibitor 11 1.5.4 Rapamycin inhibitor 11 1.5.5 Heat shock protein 90 inhibitor 11 1.5.6 Pan-HER2 tyrosine kinase inhibitor 12 1.5.7 Radioimmunotherapy 12 1.5.8 HER2 specific affinity proteins 13 1.5.9 HER2 peptide nelipepimut-S vaccine 14 1.6 Diagnosis of breast cancer 14 1.7 specific aim 15 Chapter 2 Materials and Methods 17 2.1 Cell lines and culture 17 2.2 Determination monoclonal antibodies class and subclass 17 2.3 Anti-HER2 mAbs production and purification 18 2.4 Construction and expression of trastuzumab (Herceptin) 19 2.5 Enzyme-linked immunosorbent assay (ELISA) 20 2.6 Flow cytometry 21 2.7 Apoptosis assays 22 2.8 Western blotting 22 2.9 Immunohistochemistry 23 2.10 Conjugation of fluorescence dye to the Fc domain of anti-HER-2 mAbs, trastuzumab 24 2.11 Endocytosis assay of anti-HER2 mAbs and trastuzumab 25 Chapter 3 Results 27 3.1 The class and subclass of anti-HER2 mAbs 27 3.2 Anti-HER2 mAbs specificity verifications by Western blotting 27 3.3 Immunohistochemical localization of anti-HER2 mAbs in xenograft and human breast cancer tissue array 28 3.4 Screening and confirming anti-HER2 mAbs with apoptotic ability 29 3.5 Generation of anti-HER2 monoclonal antibodies 29 3.6 Characterization of mAbs against HER2 using ELISA 30 3.7 Construction and expression of trastuzumab (Herceptin) 31 3.8 Flow cytometric analysis of anti-HER2 mAbs and trastuzumab binding to SKBR3 cells 31 3.9 The comparison of apoptotic ability between the purified anti-HER2 mAbs and trastuzumab 32 3.10 The molecular mechanism of the cancer cell apoptosis induced by anti-HER2 mAbs 32 3.11 The endocytosis ability of the anti-HER2 mAbs 33 Chapter 4 Discussions and conclusions 35 References 65 Table 1. Subclass determination of 83 anti-HER2 hybridoma clones. 40 Table 2. Summary of mAbs against HER2-Fc protein and SKBR3 cells using Western blotting. The symbol indicated in this summary. 41 Table 3. Screening of apoptotic effects of anti-HER2 mAbs. 42 Table 4. Screening endocytosis ability of anti-HER2 mAbs. 43 Figure 1. Western blot analysis of anti-HER2 mAbs. 46 Figure 2. Identification of HER2 expression derived from xenograft tumors using immunohistochemistry. 47 Figure 3. Identification of HER2 expression derived from human breast cancer tissue array using immunohistochemistry. 48 Figure 4. Identification of apoptotic scenario of anti-HER2 mAbs. 49 Figure 5. Production and purification of anti-HER2 mAbs. 50 Figure 6. Characterization of mAbs against HER2 using ELISA. 52 Figure 7. ELISA screening for HER family members with anti-HER2 mAbs. 53 Figure 8. Construction and expression of trastuzumab (Herceptin). 54 Figure 9. Flow cytometric analysis of purified anti-HER2 mAbs binding to SKBR3 cells. 55 Figure 10. Identification of apoptotic effects of anti-HER2 mAbs in SKBR3 cells. 57 Figure 11. Identification of apoptotic effects of anti-HER2 mAbs in MBA-MB-231 cells. 59 Figure 12. Apoptotic analysis after anti-HER2 mAbs treatment. 60 Figure 13. Illustration of anti-HER2 mAbs endocytosis using confocal microscopy. 61 Figure 14. Comparison of binding and internalization activity with anti-HER2 mAbs. 62 Figure 15. To screen and to select the four highest internalized ability using endocytosis assay from 83 anti-HER2 mAbs. 64 | |
dc.language.iso | en | |
dc.title | HER2單株抗體於癌症的診斷與治療應用之探討 | zh_TW |
dc.title | Study of Monoclonal Antibodies against HER2 for Cancer Diagnosis and Therapy Applications | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 呂仁(Jean Lu),林國儀(Kuo-I Lin),蕭培文(Pei-Wen hsiao) | |
dc.subject.keyword | 乳癌,HER2,單株抗體,治療性抗體,標靶治療, | zh_TW |
dc.subject.keyword | breast cancer,HER2,monoclonal antibody,therapeutic antibody,target therapy, | en |
dc.relation.page | 72 | |
dc.identifier.doi | 10.6342/NTU201601807 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2016-08-05 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 病理學研究所 | zh_TW |
顯示於系所單位: | 病理學科所 |
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