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研究生： 王瑋祥
Wang, Wei-Shyang
論文名稱： 使用非侵犯性活體照影評估介白素八調控子控制之溶瘤腺病毒在原位肺腺癌之療效
Evaluation of the therapeutic effects of interleukin- 8-dependent oncolytic adenovirus on orthotopic lung adenocarcinoma by in vivo non-invasive imaging
指導教授： 蕭璦莉
Shiau, Ai-Li
學位類別： 碩士
Master
系所名稱： 醫學院 - 微生物及免疫學研究所
Department of Microbiology & Immunology
論文出版年： 2007
畢業學年度： 95
語文別： 中文
論文頁數： 51
中文關鍵詞： 溶瘤腺病毒 、原位肺腺癌模式 、非侵犯性活體照影 、介白素八 、非小細胞肺癌
外文關鍵詞： in vivo non-invasive imaging, Oncolytic adenoviruse, orthotopic lung adenocarcinoma models, Non-small cell lung cancer, Interleukin-8
相關次數： 點閱：178  下載：1 
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    • 非小細胞肺癌是最常發生的惡性腫瘤之一，約占所有肺癌的百分之八十。然大部分非小細胞肺癌的病人為晚期肺癌，而至今沒有任何較有效的治療可供選擇。因此，新療法的研究是當前迫切需要的。而溶瘤腺病毒(oncolytic virus)正是目前針對許多癌症脫穎而出的嶄新治療藥物。介白素八(interleukin-8, IL-8)現今被認為是一種在許多癌症中(包括非小細胞肺癌)由腫瘤細胞分泌並能作用於該腫瘤及周遭細胞的血管新生及生長因子。此外，肺癌細胞的介白素八表現量也與血管新生、癌症進程、轉移及低存活率相關。而在腫瘤浸潤的巨噬細胞則會透過分泌的第一腫瘤壞死因子(tumor necrosis factor-α, TNF-α)及介白素一(interleukin-1, IL-1)，經由NF-κB路徑增加腫瘤表現介白素八。而在腫瘤的微環境中的介白素八除了由腫瘤分泌外，巨噬細胞與基細胞(stromal cells)也參與其中。因此，在非小細胞肺癌中以介白素八調控子控制溶瘤腺病毒應可具有更佳的腫瘤專一性與溶瘤效果。現今認為介白素八調控子(promoter)上的必須最小區域包含有AP-1、NF-ΚB及C/EBP-β三個主要的轉錄因子結合位。據此，在本研究中，我們建構了以人類介白素八調控子(-1481~+44)驅動的E1B 55kD缺失溶瘤腺病毒(Ad.WSW)，並測試其在非小細胞肺癌中的療效。 我們證明相較其他癌症細胞株，介白素八調控子在人類肺腺癌A549及小鼠肺癌Lewis lung carcinoma細胞株中有較強的活性。藉此，Ad.WSW在人類及小鼠的肺癌細胞中具有毒殺作用，而且毒殺效果可進一步的藉由TNF-α所增強。同時，Ad.WSW具有選擇性在腫瘤細胞複製的能力，而不論在人類或小鼠正常細胞中皆無毒殺作用。在原位肺癌的小鼠模式中，我們利用穩定表現螢火蟲冷光的A549及Lewis lung carcinoma 細胞株及非侵犯性活體照影系統，建立了在NOD/SCID或C57BL/6小鼠活體偵測原位肺癌發展的技術。利用此技術，精確的證明Ad.WSW能有效地抑制小鼠原位肺癌的生長並延長小鼠的壽命。由以上結果結論，以介白素八調控子驅動的E1B 55kD缺失溶瘤腺病毒有潛力作為有效且安全的肺癌治療選擇。

    Non-small cell lung cancer (NSCLC), which comprises 80% of all lung cancer cases, is one of the most common human malignancies. The majority of NSCLC patients have incurable advanced disease with very poor therapeutic option. Therefore, new treatment approaches are urgently needed. Oncolytic adenoviruses have emerged as novel therapeutic agents for a variety of cancers. Interleukin-8/CXCL8 (IL-8) has been shown to be an angiogenic and growth factor, either autocrine or paracrine, in several cancers, including NSCLC. Moreover, the expression level of IL-8 in lung cancer is associated with angiogenesis, tumor progression, metastasis, and poor survival. Infiltrating macrophages may up-regulate tumor IL-8 expression through the NF-κB pathway and modulation by tumor necrosis factor-α (TNF-α) and interleukin-1. In the NSCLC microenvironment, IL-8 can be secreted from tumor cells, macrophages, and stromal cells. It is, therefore, feasible to exploit IL-8 promoter to control the replication of oncolytic adenovirus aiming to achieve more tumor-targeted oncolysis for treating NSCLC. Characterization of IL-8 promoter indicated that the minimal region essential for IL-8 expression contains the binding sites of AP-1, NF-κB, and C/EBP-β (NF-IL-6). Based on these observations, in this study we constructed an E1B 55kD-deleted oncolytic adenovirus driven by the human IL-8 promoter (-1481~+44), designated Ad.WSW, and tested its oncolytic activity for the treatment of NSCLC. Ad.WSW caused cytolytic effects in murine and human lung cancer cells with high IL-8 promoter activity, which could be further enhanced by TNF-α treatment. Ad.WSW also selectively replicated in murine and human lung cancer cell lines but not in normal cells. Moreover, we used A549 and Lewis lung carcinoma cells stably expressing firefly luciferase (A549-luc and LL-luc) to establish orthotopic lung adenocarcinoma models in NOD/SCID and C57BL/6 mice, respectively, which were useful for monitoring intrapleural lung tumors by in vivo bioluminescence imaging. Using in vivo non-invasive imaging, we found Ad.WSW alone reduced tumor burdens and prolonged survival in the orthotopic A549 lung tumor model. We concluded that IL-8 promoter-driven oncolytic virus has the potential to be an effective strategy for lung cancer treatment.

    Chinese abstract…………………………………Ⅰ Abstract……………………………………………Ⅲ Acknowledgement…………………………………Ⅴ Content………………………………………………Ⅵ Figure content………………………………………Ⅸ Abbreviation…………………………………………Ⅹ Introduction Non-small-cell lung cancer (NSCLC) and malignant pleural effusion (MPE)………1 Relationship between interleukin-8 (IL-8), IL-8 promoter, and cancer…………2 Life cycle of adenovirus and oncolytic adenovirus therapy ………………………3 Orthotopic murine model of lung adenocarcinoma and non-invasive imaging………5 Materials and Methods Materials Plasmids…………………………………………………………7 Oligonucleotides………………………………………………7 Cell lines………………………………………………………8 Aminals…………………………………………………………9 Methods Cell lines and cell culture………………………………………………………………9 Cloning of human IL-8 promoter and construction of IL-8 reporter plasmid……10 Assay of the transcriptional activity of promoters…………………………………10 Construction and generation of IL-8 promoter-driven oncolytic Ad (Ad.WSW)…11 Determination of viral titer………………………………………………………………11 Viral replication and cytopathic effect (CPE) assays……………………………12 Animal experiments Monitoring of tumor growth in pleural cavity by in vivo bioluminescence imaging………………………………………………………………………………………12 Antitumor effects of Ad.WSW on an orthotopic lung adenocarcinoma murine model…………………………………………………………………………………………12 Statistical analysis………………………………………………………………………13 Results Cloning of human IL-8 promoter and construction of IL-8 reporter plasmid…14 The IL-8 promoter activities in human and murine cancer cell lines…………14 The promoter activities of IL-8 in TNF-α-treated or Ad.null-infected human cell lines……………………………………………………………………………………15 Enhancement of the IL-8 promoter activity by chemotherapeutic agents in lung cancer cells resulted in increased Ad.WSW replication…………………………15 Construction of oncolytic adenovirus driven by the IL-8 promoter……………16 Cytolytic effects of Ad.WSW on human (murine) cancer and normal cell lines…16 Cytolytic effects of Ad.WSW on different human lung cancer cells lines with different IL-8 promoter activity………………………………………………………17 Establishment of non-invasive imaging for an orthotopic murine model of lung cancer…………………………………………………………………………………………18 Cytolytic effects of Ad.WSW on an orthotopic murine model of human lung adenocarcinoma………………………………………………………………………………18 Discussion……………………………………………………………20 References……………………………………………………………25 Figure content Fig. 1 Cloning of the human IL-8 promoter and construction of the IL-8 reporter plasmid pFRL2 IL-8-Luc……………………………………………32 Fig. 2 The promoter activities of IL-8 in human and murine cancer cell lines………………………………………………………………………………33 Fig. 3 The promoter activities of IL-8 in TNF-α-treated or Ad.null- infected human cell line…………………………………………………………34 Fig. 4 The promoter activities of IL-8 in A549 cells treated with different chemotherapeutic agents.………………………………………………………35 Fig. 5 Genomic structure and characterization of Ad.WSW (IL-8 promoter- E1A-E1B 55kD-deleted)…………………………………………………………36 Fig. 6 Cytolytic effects of Ad.WSW on human A549 lung cancer cells and HEL299 normal lung fibroblasts…………………………………………37 Fig. 7 Cytolytic effects of Ad.WSW on murine LL2 lung cancer cells and NIH3T3 normal fibroblasts……………………………………………………38 Fig. 8 Cytolytic effects of Ad.WSW on different human lung cancer cells with different IL-8 promoter activities…………………………………39 Fig. 9 Monitoring of tumor growth in pleural cavity by in vivo bioluminescence imaging………………………………………………………40 Fig. 10 Therapeutic efficacy of Ad.WSW in treating A549-luc orthotopic human lung tumor xenograft in SCID mice………………………………41

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