64Cu-ATSM reflects pO2 levels in human head and neck cancer xenografts but not in colorectal cancer xenografts: Comparison with 64CuCl2

Abstract

The hypoxia PET tracer 64Cu-diacetyl-bis(N4-methylthiosemicarbazonate) (64Cu-ATSM) has shown promising results in clinical studies. However, concerns have been raised with regard to the possible effect of copper metabolism and free copper on tumor uptake and thereby the robustness of 64Cu-ATSM as a hypoxia marker. In this study, accumulation and distribution of 64Cu-ATSM and 64CuCl2 in tumor tissue were compared with partial pressure of oxygen (pO2) probe measurements. Methods: One-hour dynamic PET scans were performed on nude mice bearing subcutaneous human head and neck tumors (FaDu) and human colorectal tumors (HT29) after administration of either 64Cu-ATSM or 64CuCl2. Subsequently, tracks were generated and track markers were positioned in tumors to allow for registration of their exact location on the high-resolution CT scan. After completion of the CT scan, pO2 probe measurements were performed along each track. PET and CT images were coregistered and ROIs drawn on the basis of the location of track markers and pO2 probe measurement depth. A linear mixed model for repeated measures was applied for the comparison of PET tracer uptake to corresponding pO2 values. Results: Comparable uptake of 64Cu-ATSM and 64CuCl2 was found in the kidney, muscle, and liver of all animals, but 64CuCl2 showed a higher uptake 10- 60 min after injection in both tumor models. Significant differences were also found for both tumor-to-muscle and tumor-to-liver ratios. The intratumoral distribution of 64Cu-ATSM, but not 64CuCl2, showed a significant negative relationship with pO2 measurements in FaDu tumors. However, this relationship was not found in HT29 tumors. Conclusion: 64Cu-ATSM and 64CuCl2 displayed different uptake in tumors. In human head and neck xenografts, 64Cu-ATSM but not 64CuCl2 reflected pO2 measurements, indicating that 64Cu- ATSM is a hypoxia-specific marker in this tumor type. However, data from colorectal cancer xenografts indicated that 64Cu-ATSM may not be a hypoxia marker in all tumor types.