Radio-copper-labeled Cu-ATSM: an indicator of quiescent but clonogenic cells under mild hypoxia in a Lewis lung carcinoma model

The purpose of this study is to reveal characteristics of 64Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone) ([64Cu]Cu-ATSM) during cell proliferation and hypoxia by autoradiography imaging and immunohistochemical staining.MethodsThe intratumoral distributions of [64Cu]Cu-ATSM and [18F]-2-fluoro-2-deoxy-D-gloucose ([18F]FDG) in mice implanted with Lewis lung carcinoma (LLC1) tumor cells according to dual autoradiography were compared with the immunohistochemical staining patterns of proliferating markers [Ki-67 and 5-bromo-2′-deoxyuridine (BrdU)] and a hypoxic marker (pimonidazole). A clonogenic assay was performed using the cells of LLC1 tumor-implanted mice, and it was compared with the distribution of [64Cu]Cu-ATSM.Results[64Cu]Cu-ATSM mainly accumulated at the edge of tumors, whereas [18F]FDG was distributed inside the tumor and inside the [64Cu]Cu-ATSM accumulation. The number of Ki-67-positive cells/area tended to increase with [18F]FDG accumulation and decrease with [64Cu]Cu-ATSM accumulation. On the other hand, the number of BrdU-positive cells/area was negatively correlated with [18F]FDG accumulation and positively correlated with [64Cu]Cu-ATSM accumulation. High [64Cu]Cu-ATSM accumulation was found outside the high-[18F]FDG-accumulation and pimonidazole-positive regions. Colony formation ability was significantly higher in the tumor cells obtained from high-[64Cu]Cu-ATSM-accumulation regions than the cells from the intermediate- and the low-accumulation regions.Conclusion[64Cu]Cu-ATSM accumulation regions in tumor cells indicate quiescent but clonogenic tumor cells under mild hypoxia. [64Cu]Cu-ATSM could play an important role in planning appropriate tumor radiotherapy.