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

UNLABELLED: The purpose of this study is to reveal characteristics of (64)Cu-labeled diacetyl-bis(N(4)-methylthiosemicarbazone) ([(64)Cu]Cu-ATSM) during cell proliferation and hypoxia by autoradiography imaging and immunohistochemical staining.
METHODS: The intratumoral distributions of [(64)Cu]Cu-ATSM and [(18)F]-2-fluoro-2-deoxy-D-glucose ([(18)F]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 [(64)Cu]Cu-ATSM.
RESULTS: [(64)Cu]Cu-ATSM mainly accumulated at the edge of tumors, whereas [(18)F]FDG was distributed inside the tumor and inside the [(64)Cu]Cu-ATSM accumulation. The number of Ki-67-positive cells/area tended to increase with [(18)F]FDG accumulation and decrease with [(64)Cu]Cu-ATSM accumulation. On the other hand, the number of BrdU-positive cells/area was negatively correlated with [(18)F]FDG accumulation and positively correlated with [(64)Cu]Cu-ATSM accumulation. High [(64)Cu]Cu-ATSM accumulation was found outside the high-[(18)F]FDG-accumulation and pimonidazole-positive regions. Colony formation ability was significantly higher in the tumor cells obtained from high-[(64)Cu]Cu-ATSM-accumulation regions than the cells from the intermediate- and the low-accumulation regions.
CONCLUSION: [(64)Cu]Cu-ATSM accumulation regions in tumor cells indicate quiescent but clonogenic tumor cells under mild hypoxia. [(64)Cu]Cu-ATSM could play an important role in planning appropriate tumor radiotherapy.