Potent effect of adenoviral vector expressing short hairpin RNA targeting ribonucleotide reductase large subunit M1 on cell viability and chemotherapeutic sensitivity to gemcitabine in non-small cell lung cancer cells

• Material Type: 博士論文
• Title: Potent effect of adenoviral vector expressing short hairpin RNA targeting ribonucleotide reductase large subunit M1 on cell viability and chemotherapeutic sensitivity to gemcitabine in non-small cell lung cancer cells
• Author/Editor: 徳永, 義昌
• Author Heading: 徳永, 義昌
• Publication Date: 2016-03-24
• Publication Date (W3CDTF): 2016-03-24
• Degree grantor/type: 香川大学
• Date Granted: 2016-03-24
• Date Granted (W3CDTF): 2016-03-24
• Dissertation Number: 甲第621号
• Degree Type: 博士（医学）
• Conferring No. (Dissertation): 甲第621号
• Text Language Code: eng
• Alias of Author: Tokunaga, Yoshimasa
• Subject Heading: RRM1; shRNA; Adenovirus; Gene therapy; Gemcitabine; Chemotherapeutic sensitivity
• Target Audience: 一般
• Note (General): Background: Ribonucleotide reductase large subunit (RRM1) is the main enzyme responsible for synthesis of the deoxyribonucleotides used during DNA synthesis. It is also a cellular target for gemcitabine (GEM). Overexpression of RRM1 is reportedly associated with resistance to GEM and the poor prognosis for many types of malignant tumours. Aim of the present study is to establish gene therapy against RRM1-overexpressing tumours.; Method: An adenoviral vector that encoded a short hairpin siRNA targeting the RRM1 gene (Ad-shRRM1) was constructed. Two RRM1-overexpressing non-small cell lung cancer (NSCLC) lines, MAC10 and RERF-LC-MA, were used. Finally, a human tumour xenograft model in nude mice was prepared by subcutaneously implanting tumours derived from RERF-LC-MA cells.; Results: Ad-shRRM1 effectively downregulated RRM1 mRNA and protein in both types of NSCLC cells and significantly reduced the percentage of viable cells as detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (p<0.005). Caspase 3/7 analysis revealed that transfection with Ad-RRM1 increased the percentage of apoptotic cells in culture containing either type of RRM1-overexpressing cell (p<0.001). Treatment with Ad-shRRM1 exerted a potent antitumour effect against the RRM1-overexpressing RERF-LC-MA xenografts (p<0.05). Furthermore, Ad-shRRM1-mediated inhibition of RRM1 specifically increased sensitivity to gemcitabine of each type of RRM1-overexpressing tumour cell. Combination treatment with Ad-shRRM1 and GEM exerted significantly greater inhibition on cell proliferation than Ad-shRRM1 or GEM treatment alone.; Conclusion: RRM1 appeared to be a promising target for gene therapy, and Ad-shRRM1 had strong antitumour effects, specifically anti-proliferative and pro-apoptotic effects, against NSCLC cells that overexpressed RRM1. Combination therapy with Ad-shRRM1 and GEM may become a new treatment option for patients with NSCLC.
• DOI: info:doi/10.1016/j.ejca.2015.05.013; https://doi.org/info:doi/10.1016/j.ejca.2015.05.013
• Persistent ID (NDL): info:ndljp/pid/11337525; https://dl.ndl.go.jp/pid/11337525
• Collection (particular): 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文; https://dl.ndl.go.jp/collections/A00014
• Acquisition Basis: 博士論文（自動収集）
• Date Accepted (W3CDTF): 2019-08-03T12:23:27+09:00
• Date Created (W3CDTF): 2020-10-27
• Format (IMT): PDF
• Access Restrictions: 国立国会図書館内限定公開
• Service for the Digitized Contents Transmission Service: 図書館・個人送信対象外
• Availability of remote photoduplication service: 可
• Periodical Title (URI): https://kagawa-u.repo.nii.ac.jp/records/375
• Data Provider (Database): 国立国会図書館 : 国立国会図書館デジタルコレクション; https://dl.ndl.go.jp