RT Journal Article
SR Electronic
T1 Intertumoral Differences in Hypoxia Selectivity of the PET Imaging Agent <sup>64</sup>Cu(II)-Diacetyl-Bis(<em>N</em><sup>4</sup>-Methylthiosemicarbazone)
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 989
OP 998
VO 47
IS 6
A1 Hong Yuan
A1 Thies Schroeder
A1 James E. Bowsher
A1 Laurence W. Hedlund
A1 Terence Wong
A1 Mark W. Dewhirst
YR 2006
UL http://jnm.snmjournals.org/content/47/6/989.abstract
AB 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.