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Auger electron radioimmunotherapy using 111In-nuclear localizing anti-HER2 antibody: A cell biological study
https://repo.qst.go.jp/records/71502
https://repo.qst.go.jp/records/7150272f5a39b-2f48-4682-adc6-85c8a0eb3393
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2014-09-29 | |||||
| タイトル | ||||||
| タイトル | Auger electron radioimmunotherapy using 111In-nuclear localizing anti-HER2 antibody: A cell biological study | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_c94f | |||||
| 資源タイプ | conference object | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Hasegawa, Sumitaka
× Hasegawa, Sumitaka× Furukawa, Takako× Saga, Tsuneo× 長谷川 純崇× 古川 高子× 佐賀 恒夫 |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Objective: Auger electrons have a potential for effective cell killing when the radionuclide is delivered into cell nucleus and located to close to DNA. The use of nuclear localizing signal (NLS) has been proposed to transport Auger-electron emitters to the cell nucleus of tumor cells. To explore the capability of nuclear localized 111In, an Auger-electron emitter, to bring cell ablation to the targeted human cancer cells overexpressing HER2, we evaluated the cytotoxicity of the 111In-labeled anti-HER2 antibody attached with peptides containing NLS derived from simian virus 40, to human breast cancer cells overexpressing HER2. Materials and methods: Trastuzumab, an anti-HER2 antibody, was conjugated with CHX-A’’-DTPA (DTPA) for 111In labeling and derivatized with sulfosuccinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sulfo-SMCC) to react with 13-mer peptides containing a NLS sequence (CGYGPKKKRKVGG). Two types of NLS-trastuzumab were generated; one carried approximately 4 NLS peptides per antibody (NLS-trastuzumab-S) and another carried 10 (NLS-trastuzumab-L). NLS-trastuzumab-DTPA conjugates and trastuzumab-DTPA were labelled with 111In. Radiochemical labelling of 111In-NLS-trastuzumab and 111In-trastuzumab was evaluated by HPLC. Nuclear accumulation of 111In was measured in NIH-3T3 cells overexpressing human HER2 by subcellular fraction. Cell survival was evaluated by colony-forming assays in NIH-3T3 cells overexpressing human HER2. Cell viability was tested by dye-based cell viability assays in human mammary epithelial cells (HMEpC) and two types of human mammary carcinoma cells, MCF-7 and SK-BR-3 cells with a low and a high expression of HER2, respectively. DNA damages were examined in SK-BR-3 cells by γ-H2AX immunohistochemistry. Results: Nuclear uptake of 111In was increased 1.5-fold and 1.3-fold in cells treated with 111In-NLS-trastuzumab-L and 111In-NLS-trastuzumab-S compared to 111In-trastuzumab, respectively. The clonogenic survival of NIH-3T3 cells overexpressing human HER2 was decreased when treated with 111In-NLS-trastuzumab-L compared to 111In-trastuzumab. Cell viability was significantly reduced with both of 111In-NLS-trastuzumab-L and S (462.5 and 231.25 kBq) compared to 111In-trastuzumab in SK-BR-3 cells with a high expression of HER2. Both of 111In-NLS-trastuzumab had little or no antiproliferative effects on MCF-7 cells and HMEpC that expressed a low level of HER2 protein. Increased number of γ-H2AX foci were found in SK-BR-3 cells reacted with 111In-NLS-trastuzumab-L compared to 111In-trastuzumab. Conclusions: The cytotoxic and antiproliferative effects of 111In-NLS-trastuzumab are higher than 111In-trastuzumab in HER2-overexpressing human mammary carcinoma cells. These data demonstrate that delivery of 111In into cell nucleus by anti-HER2 antibody harboring NLS is an effective strategy for targeted cell killing of the human cancer cells overexpressing HER2. |
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| 会議概要（会議名, 開催地, 会期, 主催者等） | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | 11th Congress of the World Federation of Nuclear Medicine and Biology | |||||
| 発表年月日 | ||||||
| 日付 | 2014-08-30 | |||||
| 日付タイプ | Issued | |||||
