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アイテム
Combined treatment of pancreatic cancer xenograft with 90Y-ITGA6B4-mediated radioimmunotherapy and PI3K/ mTOR inhibitor
https://repo.qst.go.jp/records/49284
https://repo.qst.go.jp/records/4928495cf8982-aac4-4201-bdd5-abd9ec46a4f7
| Item type | 学術雑誌論文 / Journal Article(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2018-11-27 | |||||
| タイトル | ||||||
| タイトル | Combined treatment of pancreatic cancer xenograft with 90Y-ITGA6B4-mediated radioimmunotherapy and PI3K/ mTOR inhibitor | |||||
| 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_6501 | |||||
| 資源タイプ | journal article | |||||
| 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 |
Winn, Aung
× Winn, Aung× Tsuji, Atsushi× Sudo, Hitomi× Sugyo, Aya× Ukai, Yoshinori× Kouda, Katsushi× Kurosawa, Yoshikazu× Furukawa, Takako× Saga, Tsuneo× Higashi, Tatsuya× Ｕ Ｗｉｎｎ Ａｕｎｇ× 辻 厚至× 須藤 仁美× 須尭 綾× 東 達也 |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | AIM To investigate the therapeutic effect of combined integrin α6β4-targeted radioimmunotherapy (RIT) and PI3K/mTOR inhibitor BEZ235 in a pancreatic cancer model. METHODS Phosphorylation of Akt, mTOR, the downstream effectors eukaryotic initiation factor 4E binding protein 1 (4EBP1) and S6 ribosomal protein (S6) were evaluated in BxPC-3 human pancreatic cancer cells treated with Yttrium-90 (90Y) labeled anti-integrin α6β4 antibody (ITGA6B4) and BEZ235 by western blotting. The cytotoxic effect of BEZ235 was investigated using a colony formation assay. Therapeutic efficacy enhancement by oral BEZ235 administration was assessed using mice bearing BxPC-3 xenograft tumors. Tumor volume measurements and immunohistochemical analyses (cell proliferation marker Ki-67, DNA damage marker p-H2AX and p-4EBP1 staining) of tumors were performed for evaluation of combined treatment with 90Y-ITGA6B4 plus BEZ235, or each arm alone. RESULTS We found that phosphorylation of Akt (p-Akt), 4EBP1 (p-4EBP1) and S6 (p-S6) was inhibited by BEZ235. Colony formation in BxPC-3 cells was additively suppressed by the combination of 90Y-ITGA6B4 and BEZ235. Pretreatment with BEZ235 before 90Y-ITGA6B4 exposure resulted in significant reduction of cells plating efficiency (PE) (0.54 ± 0.11 vs 2.81 ± 0.14 with 185 kBq/mL 90Y-ITGA6B4 exposure, P < 0.01; 0.39 ± 0.08 vs 1.88 ± 0.09 with 370 kBq/mL 90Y-ITGA6B4 exposure, P < 0.01) when 5 × 103 cells per dish were plated. In vivo , the combined treatment with 90Y-ITGA6B4 plus BEZ235 enhanced the inhibition of tumor growth and statistically significant differences of relative tumor volume were observed for 27 d after the treatment start date when compared with the 90Y-ITGA6B4 single injection treatment (1.03 ± 0.38 vs 1.5 ± 0.15 at Day 27, P < 0.05), and for 41 d when compared with the BEZ235 treatment alone (1.8 ± 0.7 vs 3.14 ± 1.19 at Day 41, P < 0.05). Tumors from treatment groups showed reduction in volumes, decreased Ki-67-positive cells, increased p-H2AX-positive cells and decreased p-4EBP1 expression. CONCLUSION The therapeutic efficacy of 90Y-ITGA6B4-RIT can be improved by combining with dual PI3K and mTOR inhibitor, BEZ235, in a pancreatic cancer model suggesting potential clinical application. Key words: Radioimmunotherapy; Pancreatic cancer; anti-integrin α6β4 antibody; Yttrium-90; NVP-BEZ235 |
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| 書誌情報 |
World Journal of Gastroenterology 巻 23, 号 42, p. 7551-7562, 発行日 2017-11 |
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| 出版者 | ||||||
| 出版者 | Baishideng Publishing Group Inc | |||||
| ISSN | ||||||
| 収録物識別子タイプ | ISSN | |||||
| 収録物識別子 | 1007-9327 | |||||
| PubMed番号 | ||||||
| 識別子タイプ | PMID | |||||
| 関連識別子 | 29204055 | |||||
| DOI | ||||||
| 識別子タイプ | DOI | |||||
| 関連識別子 | 10.3748/wjg.v23.i42.7551 | |||||
