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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 賴逸儒 | |
dc.contributor.author | Chuan-Yeuh Chang | en |
dc.contributor.author | 張傳約 | zh_TW |
dc.date.accessioned | 2021-06-16T10:37:55Z | - |
dc.date.available | 2016-09-24 | |
dc.date.copyright | 2013-09-24 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-08-13 | |
dc.identifier.citation | Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH and Semenza GL. Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 61: 2911–2916 (2001)
American Cancer Society. Global Cancer Facts & Figures 2nd Edition. Atlanta: American Cancer Society (2011) pp. 19-21 Baba AI, Catoi C. Comparative Oncology. Bucharest: The Publishing House of the Romanian Academy, Chapter 3 Tumor Cell Morphology (2007) Available from: http://www.ncbi.nlm.nih.gov/books/NBK9553/ Baek JH, Jang JE, Kang CM, Chung HY, Kim ND, Kim KW. Hypoxia-induced VEGF enhances tumor surviva- bility via suppression of serum deprivation-induced apoptosis. Oncogene 19: 4621–4631 (2000) Bang YJ, Cutsem EV, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK, for the ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastrooesophageal junction cancer(ToGA): a phase 3, open-label, randomised controlled trial. Lancet;376:687–97 (2010) Barnhill RL, Piepkorn MW, Cochran AJ, Flynn E, Karaoli T and Folkman J. Tumor vascularity, proliferation, and apoptosis in human melanoma micrometastases and macrometastases. J Arch Dermatol 134: 991–994 (1998) Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, Miles D, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2- positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 28:1138–1144 (2010) Carmeliet P, Do Y, Herbert JM, Fukumura D, Brusselmans K, DewerchinM, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch, CJ, Ratcliffe P, Moons L, Jain RK, Collen D and Keshet E. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394(6692): 485–490 (1998) Clifford A and Hudis MD. Trastuzumab-mechanism of action and use in clinical practice. N Engl J Med 357:39-51 (2007) Durand RE and Raleigh JA. Identification of nonproliferating but viable hypoxic tumor cells in vivo. Cancer Res. 58(16):3547-3550 (1998) Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX. Insights into ErbB signaling from the structure of the ErbB2- pertuzumab complex. Cancer Cell 5: 317– 328 (2004) Gardner LB, Li Q, Park MS, Flanagan WM and Gregg L. Hypoxia Inhibits G1/S transition through Regulation of p27 Expression. J Biol Chem 276:7919-7926 (2001) Gravalos C and Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Annals of Oncology 19: 1523–1529 (2008) Griffiths EA, Pritchard SA, Welch IM, Price PM, West CM. Is the hypoxia-inducible factor pathway important in gastric cancer ? European Journal of Cancer 41: 2792–2805 (2005) Hockel M and Vaupel P. Tumor hypoxia: definitions and current clinical, biologic and molecular aspects. J Natl Cancer Inst 93: 266–276 (2001) Horre !e E, Gort EH, van der Groep P, Heintz APM, Vooijs M and van Diest PJ. Hypoxia-inducible factor 1! is essential for hypoxic p27 induction in endometrioid endometrial carcinoma. J Pathol 214: 38–45 (2008) Ivan M, Kondo K, Yang H, Kim W and Valiando J. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292: 464–468. (2001) Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292: 468–472 (2001) Kennedy AS, Raleigh JA, Perez GM, Calkins DP, Thrall DE, Novotny DB and Varia MA. Proliferation and hypoxia in human squamous cell carcinoma of the cervix: First report of combined immunohistochemical assays. Int J Radiat Oncol Biol Phys 37: 897–905 (1997) Ke Q, Costa M. Hypoxia-Inducible Factor-1 (HIF-1). Molecular Pharmacology 70: 1469-1480 (2006) Park SY, Billiar TR and Seol DW. Hypoxia inhibition of apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Biochem Biophys Res Commun 291: 150–153 (2002) Pazo Cid RA and Anton A. Advanced HER2-positive gastric cancer: Current and future targeted therapies. Crit Rev Oncol/Hematol 85(3):350-62 (2013)doi: 10.1016/j.critrevonc.2012.08.008. Epub 2012 Sep 26. Piret JP, Mottet D, Raes M and Michiels C. CoCl2, a chemical inducer of hypoxia-inducible factor-1, and hypoxia reduce apoptotic cell death in hepatoma cell line HepG2. Ann NY Acad Sci 973: 443–447 (2002) Raleigh JA, Zeman EM, Calkins D P, McEntee MC and Thrall DE. Distribution of hypoxia and proliferation associated markers in spontaneous canine tumors. Acta Oncol. 34: 345–349 (1995) Raleigh JA, Calkins-Adams DP, Rinker LH, Ballenger CA, Weissler MC, Fowler WC Jr, Novotny DB and Varia MA. Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker. Cancer Res. 58: 3765–3768(1998) Ressel UA, Mohamed HG, Johnson RS, Nadrowitz R and Richter E. The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene 22 3213–3220 (2003) Rohwer N and Cramera T. Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resistance Updates 14:191– 201 (2011) Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J, Hasmann M. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2- positive human xenograft tumor models. Cancer Res 69: 9330–9336 (2009) Scholl S, Beuzeboc P and Pouillart P. Targeting HER2 in other tumor types. Annals of Oncology 12 (Suppl 1): S81-S87 (2001) Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A and McGuIre WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2 neu oncogene. Science,177-182, vol.235 (1987) Sun YK, Hwang PK, Yu JK, Do YO, Seock-Ah IM, Dongsoon L, Hyun-soon J, Tae-you K and Yung-Jue B. Trastuzumab inhibits the growth of human gastric cancer cell lines with HER2 amplification synergistically with cisplatin. Int J Oncology 32: 89-95 (2008) Strese S, Fryknas M, Larsson R, Gullbo J. Effects of hypoxia on human cancer cell line chemosensitivity. BMC Cancer 13:331-342 (2013) Tai W, Mahato R and Cheng K. The role of HER2 in cancer therapy and targeted drug delivery. Journal of Controlled Release 146: 264–275 (2010) Tanimoto K, Makino Y, Pereira T, Poellinger L. Mechanism of regulation of the hypoxia- inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J 19: 4298–4309 (2000) Teicher BA. Physiologic mechanisms of therapeutic resistance. Blood flow and hypoxia. Hematol Oncol Clin N Am 9: 475–506 (1995) Testa JR and Bellacosa A. AKT plays a central role in tumorigenesis. PNAS 98(20): 10983-10985 (2001) Thomlinson RH, Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9(4):539–549 (1955) Unruh A, Ressel A, Mohamed HG, Johnson RS, Nadrowitz R, Richter E, et al., The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene 22:3213–3220 (2003) Webster L, Hodgkiss RJ and Wilson GD. Cell cycle distribution of hypoxia and progression of hypoxic tumour cells in vivo. Br J Cancer 77(2): 227–234 (1998) Yamashita-Kashima Y, Iijima S, Yorozu K, et al. Pertuzumab in combination with trastuzumab shows significantly enhanced antitumor activity in HER2-positive human gastric cancer xenograft models. Clinical Cancer Research 17: 5060–5070 (2011) Yamashita-Kashima Y, Shu S, Harada N, et al. Potentiation of trastuzumab emtansine (T-DM1)-driven antitumor activity by pertuzumab in a HER2-positive gastric cancer model. J Clin Oncology 30s [Abstract e13502] (2012) Yarden Y. Biology of HER2 and tis importance in breast cancer. Oncology 61(suppl 2): 1–13 (2001) | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60948 | - |
dc.description.abstract | 在台灣,胃癌佔了國人十大死因的第五位。目前治療胃癌的方式主要是以手術輔以化學治療或是放射治療。對於某些會過量表現HER2的胃癌,近年也使用標靶藥物(Herceptin)搭配化學療法,使得癌症治療更具專一性,且減少化療導致的正常細胞受損。然而,使用標靶藥物一段時間後,胃癌常會出現對於Herceptin的抗藥性。有研究指出,腫瘤生長過程所發生的低氧(Hypoxia)情形,對癌細胞抗藥性的發生可能有重要影響。本研究的目的,在探討低氧環境對於(1)胃癌細胞生長趨勢的影響;(2)在過量表現HER2胃癌細胞株N87,使用Herceptin療效的影響,以及其可能的機制。
吾人使用體外細胞株及低氧培養箱,比較胃癌細胞株N87在正常氧及低氧環境時的生長及對Herceptin的藥效。結果顯示,在低氧的環境下,N87的形態呈現非聚合狀且細胞週期滯留於G1期。此外,利用流式細胞儀及MTT assay分析,Herceptin在低氧環境下之抑癌效果較在於正常氧壓下的效果差。 吾人並以西方墨點試驗分析HER2在低氧環境下之訊息傳遞。結果顯示,低氧環境並不影響Herceptin與HER2的聯結,但會減少Herceptin抑制p-HER2表現的現象。 再者,在正常氧壓情形下,Herceptin能有效地抑制pAKT之表現量並觀察到且p27的表現在1, 4, 8, 12小時有增加的現象。反觀,在低氧環境下,AKT與p27的磷酸化則皆不受Herceptin影響。故Herceptin在低氧環境下,對於HER2訊息傳遞並沒有抑制的效果。 從上述實驗結果可以得知,低氧環境會影響N87生長的週期,並導致標靶藥物Herceptin的抑癌效果不彰 其機制可能和低氧改變HER2之訊息傳遞有關。 | zh_TW |
dc.description.abstract | Gastric cancer ranks the 5th of the 10 leading cause of death in Taiwan in recent years. To date, the main treatment of gastric cancer, is surgery combined with chemotherapy and radiotherapy. Recently, patients with HER2-overexpressed gastric cancer are treated with target therapy (Herceptin) combined with chemotherapy, for a more specific and effective treatment but also to circumvent the cytotoxicity to normal cells. However, drug resistant develops shortly after treatment. Tumor hypoxia has been implicated as one of the underlying factors. The purposes of this study are (i) to observe the growth characteristics of a gastric cancer cell line N87 with overexpressed HER2 under hypoxia, and (ii) the efficacy of Herceptin treatment on N87 under hypoxia and possible mechanisms.
We used in vitro gastric cancer cell line N87 and hypoxia chamber to compare the cell growth and Herceptin efficacy differences between N87 cultured under normoxic and hypoxic condition. The results showed that hypoxia altered the confluent growth pattern of N87 cell, reduced proliferation rate and arrest the cell cycle progression at G1 phase. In addition, by using flow cytometry and MTT assay, the cytotoxicity of Herceptin on N87 cells is less evident under hypoxic when compare to that under normoxic condition. The Her2 signaling cascade was analyzed by Western blot. The binding of Herceptin and Her2 was not affected, but Herceptin-induced p-HER2 repression was decreased under hypoxia. In addition, the expression of pAkt, a downstream signal protein of Her2, was reduced after 1, 4, 8, and 12 hours of Herceptin treatment under normoxia; while p27 is increased at the correspondent time points. Under hypoxia, Herceptin treatment did not change the pAKT and p27 levels. The findings of this study clear suggest that hypoxic condition can affect N87 cell growth and mitigate Herceptin’s effectiveness which was related to the alteration of the HER2 signaling under hypoxia. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T10:37:55Z (GMT). No. of bitstreams: 1 ntu-102-R00446001-1.pdf: 60638104 bytes, checksum: 900a8ca531473693b59c06a40e35c118 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 口試委員會審定書................ i
誌謝.......................... ii 中文摘要....................... 1 英文摘要....................... 2 壹、緒論....................... 4 一、胃癌與傳統療法............... 4 二、標靶藥物治療................. 4 三、過量表現HER2胃癌............. 5 四、HER2....................... 6 五、胃癌標靶藥物................. 7 六、癌細胞適應低氧狀況引發之變化.... 8 七、研究目的.................... 11 貳、實驗材料...................... 12 叁、實驗方法...................... 17 肆、實驗結果...................... 24 伍、討論......................... 28 陸、附圖......................... 34 柒、參考文獻..................... 42 | |
dc.language.iso | zh-TW | |
dc.title | 低氧環境對於標靶藥物治療HER-2過量表現胃癌的影響 | zh_TW |
dc.title | The Impact of Hypoxia on Target Therapy Response in HER-2 Overexpressing Gastric Cancer | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 王淑慧,龔秀妮 | |
dc.subject.keyword | HER2,胃癌,標靶藥物,低氧,Herceptin, | zh_TW |
dc.subject.keyword | HER2,gastric cancer,target therapy,hypoxia,Herceptin, | en |
dc.relation.page | 46 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2013-08-14 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | zh_TW |
顯示於系所單位: | 解剖學暨細胞生物學科所 |
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