Internal radiotherapy with copper-64-diacetyl-bis (N4-methylthiosemicarbazone) reduces CD133+ highly tumorigenic cells and metastatic ability of mouse colon carcinoma

Introduction: Cu-64-diacetyl-bis (N-4-methylthiosemicarbazone) (Cu-64-ATSM) is an imaging agent for positron emission tomography (PET) that targets hypoxic tumors. Cu-64-ATSM is also reported to be a potential agent for internal radiotherapy. In a mouse colon carcinoma (Colon-26) model, we have shown that Cu-64-ATSM preferentially localizes in intratumoral regions with a high density of CD133(+) cells, which show characteristics of cancer stem cells or cancer stem cell-like cells (collectively referred here as CSCs). In this study, we evaluated the therapeutic effect of Cu-64-ATSM in relation to CD133 expression using this model. Methods: Systemic administration of 37 MBq Cu-64-ATSM or saline was conducted twice within a 1-week interval to mice bearing 1-week-old Colon-26 tumors (days 0-7). At day 19, tumor size measurement, flow cytometry analysis and experimental lung metastatic assay were performed. The therapeutic effect of Cu-64-ATSM on sorted CD133(+) and CD133(-) Colon-26 cells was also examined in vitro. Results: In vivo studies showed that Cu-64-ATSM treatment inhibited tumor growth. The percentage of CD133(+) cells and metastatic ability in Cu-64-ATSM treated tumors was decreased compared with that in control animals. In vitro studies demonstrated that Cu-64-ATSM accumulated in cells under hypoxic conditions and incorporation of Cu-64-ATSM under hypoxia caused cell death in both CD133(+) and CD133(-) cells in a similar extent. Conclusions: Cu-64-ATSM administration reduced tumor volume as well as the percentage of CD133(+) cells and the metastatic ability of Colon-26 tumors. Together with our data, it is suggested that Cu-ATSM accumulates in regions high in CD133(+) highly tumorigenic cells and kills such regions by radiation, resulting in a decrease of the percentage of CD133(+) cells. (C) 2011 Elsevier Inc. All rights reserved.