2016年6月
Cu-64-ATSM therapy targets regions with activated DNA repair and enrichment of CD133(+) cells in an HT-29 tumor model: Sensitization with a nucleic acid antimetabolite
CANCER LETTERS
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- 巻
- 376
- 号
- 1
- 開始ページ
- 74
- 終了ページ
- 82
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1016/j.canlet.2016.03.020
- 出版者・発行元
- ELSEVIER IRELAND LTD
Cu-64-diacetyl-bis (N-4-methylthiosemicarbazone) (Cu-64-ATSM) is a potential theranostic agent targeting the over-reduced state under hypoxia within tumors. Recent clinical Cu-ATSM positron emission tomography studies have revealed a correlation between uptake and poor prognosis; however, the reason is unclear. Here, using a human colon carcinoma HT-29 model, we demonstrated that the intratumoral Cu-64-ATSM high-uptake regions exhibited malignant characteristics, such as upregulated DNA repair and elevated %CD133(+) cancer stem-like cells. Based on this evidence, we developed a strategy to enhance the efficacy of Cu-64-ATSM internal radiotherapy (IRT) by inhibiting DNA repair with a nucleic acid (NA) antimetabolite. The results of the analyses showed upregulation of pathways related to DNA repair along with NA incorporation (bromodeoxyuridine uptake) and elevation of %CD133(+) cells in Cu-64-ATSM high-uptake regions. In an in vivo Cu-64-ATSM treatment study, co-administration of an NA antimetabolite and Cu-64-ATSM synergistically inhibited tumor growth, with little toxicity, and effectively reduced %CD133(+) cells. Cu-64-ATSM therapy targeted malignant tumor regions with activated DNA repair and high concentrations of CD133(+) cells in the HT-29 model. NA antimetabolite co-administration can be an effective approach to enhance the therapeutic effect of Cu-64-ATSM IRT. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
- リンク情報
- ID情報
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- DOI : 10.1016/j.canlet.2016.03.020
- ISSN : 0304-3835
- eISSN : 1872-7980
- Web of Science ID : WOS:000375886000008