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Intertumoral Differences in Hypoxia Selectivity of the PET Imaging Agent ⁶⁴Cu(II)-Diacetyl-Bis(N⁴-Methylthiosemicarbazone)

¹ Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina; ² Department of Radiology, Duke University Medical Center, Durham, North Carolina; and ³ Center for In Vivo Microscopy, Duke University Medical Center, Durham, North Carolina

Correspondence: For correspondence or reprints contact: Mark W. Dewhirst, DVM, PhD, Room 201 MSRB, Research Dr., Duke University Medical Center, Box 3455 DUMC, Durham, NC 27710. E-mail: dewhirst{at}radonc.duke.edu

Cu-Diacetyl-bis(N⁴-methylthiosemicarbazone) (Cu-ATSM) is a recently developed PET imaging agent for tumor hypoxia. However, its accuracy and reliability for measuring hypoxia have not been fully characterized in vivo. The aim of this study was to evaluate ⁶⁴Cu-ATSM as a hypoxia PET marker by comparing autoradiographic distributions of ⁶⁴Cu-ATSM with a well-established hypoxia marker drug, EF5. Methods: R3230 mammary adenocarcinomas (R3230Ac), fibrosarcomas (FSA), and 9L gliomas (9L) were used in the study. EF5 and Hoechst 33342, a vascular perfusion marker, were administered to the animal for immunohistochemical analysis. ⁶⁴Cu-ATSM microPET and autoradiography were performed on the same animal. The tumor-to-muscle ratio (T/M ratio) and standardized uptake values (SUVs) were characterized for these 3 different types of tumors. Five types of images—microPET, autoradiography, EF5 immunostaining, Hoechst fluorescence vascular imaging, and hematoxylin-and-eosin histology—were superimposed, evaluated, and compared. Results: A significantly higher T/M ratio and SUV were seen for FSA compared with R3230Ac and 9L. Spatial correlation analysis between ⁶⁴Cu-ATSM autoradiography and EF5 immunostained images varied between the 3 tumor types. There was close correlation of ⁶⁴Cu-ATSM uptake and hypoxia in R3230Ac and 9L tumors but not in FSA tumors. Interestingly, elevated ⁶⁴Cu-ATSM uptake was observed in well-perfused areas in FSA, indicating a correlation between ⁶⁴Cu-ATSM uptake and vascular perfusion as opposed to hypoxia. The same relationship was observed with 2 other hypoxia markers, pimonidazole and carbonic anhydrase IX, in FSA tumors. Breathing carbogen gas significantly decreased the hypoxia level measured by EF5 staining in FSA-bearing rats but not the uptake of ⁶⁴Cu-ATSM. These results indicate that some other ⁶⁴Cu-ATSM retention mechanisms, as opposed to hypoxia, are involved in this type of tumor. Conclusion: To our knowledge, this study is the first comparison between ⁶⁴Cu-ATSM uptake and immunohistochemistry in these 3 tumors. Although we have shown that ⁶⁴Cu-ATSM is a valid PET hypoxia marker in some tumor types, but not for all, this tumor type–dependent hypoxia selectivity of ⁶⁴Cu-ATSM challenges the use of ⁶⁴Cu-ATSM as a universal PET hypoxia marker. Further studies are needed to define retention mechanisms for this PET marker.

Key Words: tumor hypoxia • PET • Cu-ATSM

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