本文關(guān)鍵詞： HAb18G/CD147 美妥珠單抗 食管癌 ADCC 淋巴轉(zhuǎn)移　出處：《第四軍醫(yī)大學(xué)》2015年碩士論文　論文類型：學(xué)位論文

【摘要】：食管癌是一種常見的惡性腫瘤,根據(jù)世界衛(wèi)生組織公布的數(shù)據(jù),全世界每年有超過40萬人死于食管癌,致死人數(shù)列所有腫瘤第六位。中國是食管癌高發(fā)地區(qū)。臨床上治療食管癌的方法以手術(shù)切除為主,同時配合放療和化療。但是這些手段的療效并不理想,食管癌患者術(shù)后5年生存率不足15%。食管癌復(fù)發(fā)率很高,淋巴轉(zhuǎn)移對患者的生存造成很大威脅。近年來,分子靶向治療為食管癌患者帶來了新的希望。據(jù)報道,西妥昔單抗(Cetuximab)、曲妥珠單抗(Trastuzumab)以及貝伐珠單抗(Bevacizumab)對于食管癌均有不錯的治療效果。研究表明,HAb18G/CD147分子在食管癌等多種腫瘤組織中特異性高表達,參與并影響腫瘤發(fā)生和發(fā)展的多個過程。本實驗室研制出了以HAb18G/CD147為治療靶點的第二代抗體藥物——美妥珠單抗(Metuzumab,HcHAb18)。初步研究表明,美妥珠單抗具有較強的抗原結(jié)合能力,能有效的封閉靶細(xì)胞表面的HAb18G/CD147分子。同時,美妥珠單抗Fc段經(jīng)過特殊N-糖基化修飾,與自然殺傷細(xì)胞膜上激活性Fc受體(FcγRⅢA)的結(jié)合能力得到提高,能更加有效的激活自然殺傷細(xì)胞,分泌穿孔素和顆粒酶,殺傷腫瘤細(xì)胞。本課題的目的是:利用體內(nèi)外模型,明確美妥珠單抗對食管癌細(xì)胞生長和轉(zhuǎn)移能力的抑制作用課題主要包括以下內(nèi)容:(1)利用體內(nèi)外模型,檢測美妥珠單抗對食管癌細(xì)胞ADCC殺傷作用。(2)通過平板劃痕實驗和侵襲小室實驗考察美妥珠單抗體外抑制食管癌細(xì)胞的侵襲和遷移能力;建立食管癌裸鼠足墊移植瘤模型,檢測美妥珠單抗體內(nèi)抑制食管癌淋巴轉(zhuǎn)移能力。結(jié)果顯示:體外實驗中,美妥珠單抗與效應(yīng)細(xì)胞共同作用對食管癌細(xì)胞的ADCC殺傷率可達60%以上。在食管癌裸鼠皮下移植瘤模型實驗中,美妥珠單抗有效抑制腫瘤的生長并呈現(xiàn)劑量依賴,最高抑瘤率可達72.5%。然而,美妥珠單抗單獨作用不能抑制食管癌細(xì)胞增殖或誘導(dǎo)其發(fā)生凋亡。美妥珠在體外實驗中能有效抑制食管癌細(xì)胞的侵襲和遷移能力。在食管癌裸鼠足墊移植瘤模型實驗中,美妥珠單抗有效抑制了腫瘤遠處淋巴結(jié)轉(zhuǎn)移。結(jié)論:美妥珠單抗對于食管癌細(xì)胞具有較強的ADCC殺傷作用,能有效抑制食管癌細(xì)胞在體內(nèi)的增殖能力。美妥珠單抗能有效封閉食管癌細(xì)胞所表達的HAb18G/CD147分子,抑制食管癌細(xì)胞的侵襲、遷移能力,減少食管癌細(xì)胞遠處淋巴結(jié)轉(zhuǎn)移。美妥珠單抗有潛力成為一種新的食管癌分子靶向治療藥物。
[Abstract]:Esophageal cancer is a common malignant tumor. According to the data released by the World Health Organization, more than 400,000 people die from esophageal cancer every year in the world. China has a high incidence of esophageal cancer. The clinical treatment of esophageal cancer is mainly surgical resection, combined with radiotherapy and chemotherapy. But the efficacy of these methods is not satisfactory. The 5-year survival rate of patients with esophageal cancer is less than 15%. The recurrence rate of esophageal cancer is very high, and lymphatic metastasis poses a great threat to the survival of patients. In recent years, molecular targeted therapy has brought new hope to patients with esophageal cancer. Cetuximaba, Trastuzumaband Bevacizumab) have good therapeutic effects on esophageal carcinoma. Studies have shown that HAb18G / CD147 molecules are highly expressed in esophageal carcinoma and other tumor tissues. The second generation antibody drug, Metuzumababa HcHAb18, which was used as a target for HAb18G/CD147 treatment, was developed in our laboratory. The preliminary study showed that metozumababab has strong antigen-binding ability. At the same time, the binding ability of the mettozumab FC segment to the activated FC receptor FC 緯 R 鈪，

本文編號：1505124