A Comparison of the Imaging Characteristics and Microregional Distribution of 4 Hypoxia PET Tracers

Carlin, Sean; Zhang, Hanwen; Reese, Megan; Ramos, Nicholas; Chen, Qing; Ricketts, Sally‐Ann

doi:10.2967/jnumed.113.126615

Cited by 109 publications

(86 citation statements)

References 32 publications

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“…Sharing the same mechanism of accumulation into hypoxic cells, FAZA and pimonidazole, a commonly used hypoxia marker in histochemical studies, have been reported to show similar intratumoral distributions (11,16). This observation has been confirmed in the present study (Fig.…”

Section: Discussionsupporting

confidence: 90%

“…However, several recent studies have noted differential intratumoral distributions of Cu-ATSM and nitroimidazole compounds and raised questions on whether Cu-ATSM accumulation is truly hypoxia-dependent (10,11). In the present study, we detected a very limited overlap between areas of high accumulation of FAZA and Cu-ATSM in xenografts derived from human cancer cell lines of different origins and several CTOSs in which intratumoral distribution of PET tracers is similar to that observed in clinical studies (24).…”

Section: Discussionsupporting

confidence: 80%

“…Accumulation of both classes of PET tracers inside tumors has been reported to predict prognosis in cancer patients (4)(5)(6)(7). The intratumoral distribution of Cu-ATSM has been compared to that of FMISO or FAZA previously (8)(9)(10)(11) and both similarities and differences have been reported. In the present study, we analyzed intratumoral distributions of FAZA and Cu-ATSM in xenograft tumors induced by cancer cell lines of various origin and cancer tissue originated spheroids (CTOSs).…”

Section: Introductionmentioning

confidence: 99%

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A limited overlap between intratumoral distribution of 1-(5-fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole and copper-diacetyl-bis[N(4)-methylthiosemicarbazone]

Furukawa¹,

Yuan²,

Jin³

et al. 2015

Oncology Reports

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Abstract. Positron emission tomography (PET) imaging of tumor hypoxia provides valuable information for cancer treatment planning. Two types of PET tracers, nitroimidazole compounds and [ 62,64 Cu] copper-diacetyl-bis[N(4)-methylthiosemicarbazone] (Cu-ATSM), have been used for imaging hypoxic tumors. High accumulation of these tracers in tumors was shown to predict poor prognosis. Both similar and different intratumoral distributions of these PET tracers have been reported with some studies questioning the dependence of the Cu-ATSM accumulation on hypoxia. In the present study, we compared the intratumoral distribution and cellular uptake of 1-(5-fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole (FAZA) and Cu-ATSM. Intratumoral distributions of FAZA and Cu-ATSM compared by double tracer autoradiography in xenografts of 8 cancer cell lines and 3 cancer tissue originated spheroids (CTOSs) showed that only a limited overlap was observed between the regions with high levels of FAZA and Cu-ATSM accumulation in all the xenografts. Immunohistochemistry in the regions enriched with FAZA and Cu-ATSM in xenografts demonstrated that pimonidazole adducts were in regions that accumulated high levels of FAZA, while HIF-1α was in areas enriched with either tracer. In addition, we examined the cellular uptake of FAZA and Cu-ATSM at different levels of oxygen concentration in 4 cell lines and revealed that cellular uptake of FAZA was increased with the decrease of oxygen concentration from 20 to 2 and from 2 to 1%, while the Cu-ATSM uptake increased with the decrease of oxygen concentration from 20 to 2%, but did not increase with the decrease from 2 to 1%. Our findings indicate that intratumoral distributions of FAZA and Cu-ATSM were essentially non-overlapping and although hypoxia affects the buildup of both tracers, the accumulation of Cu-ATSM occurred at milder hypoxia compared to the conditions required for the accumulation of FAZA. Therefore, accumulation levels of FAZA and Cu-ATSM may be considered as independent biomarkers.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A limited overlap between intratumoral distribution of 1-(5-fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole and copper-diacetyl-bis[N(4)-methylthiosemicarbazone]

Furukawa¹,

Yuan²,

Jin³

et al. 2015

Oncology Reports

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show abstract

“…64 Cu-ATSM has a high tumor-to-background ratio and has shown promising results in small clinical studies, in which the tumor-to-muscle ratio was able to predict treatment outcome (11)(12)(13). However, the robustness of 64 Cu-ATSM as a marker of hypoxia has been questioned, because preclinical studies have reported temporal changes in tumor uptake and cell-type-specific differences in hypoxia selectivity (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Table 1 provides an overview of major studies using 64 Cu-ATSM in small-animal tumor xenograft models.…”

mentioning

confidence: 99%

⁶⁴Cu-ATSM Reflects pO₂ Levels in Human Head and Neck Cancer Xenografts but Not in Colorectal Cancer Xenografts: Comparison with ⁶⁴CuCl₂

Jørgensen

Forman

et al. 2015

J Nucl Med

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The hypoxia PET tracer 64 Cu-diacetyl-bis(N 4 -methylthiosemicarbazonate) ( 64 Cu-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 64 Cu-ATSM as a hypoxia marker. In this study, accumulation and distribution of 64 Cu-ATSM and 64 CuCl 2 in tumor tissue were compared with partial pressure of oxygen (pO 2 ) 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 64 Cu-ATSM or 64 CuCl 2 . 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, pO 2 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 pO 2 probe measurement depth. A linear mixed model for repeated measures was applied for the comparison of PET tracer uptake to corresponding pO 2 values. Results: Comparable uptake of 64 Cu-ATSM and 64 CuCl 2 was found in the kidney, muscle, and liver of all animals, but 64 CuCl 2 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 64 Cu-ATSM, but not 64 CuCl 2 , showed a significant negative relationship with pO 2 measurements in FaDu tumors. However, this relationship was not found in HT29 tumors. Conclusion: 64 Cu-ATSM and 64 CuCl 2 displayed different uptake in tumors. In human head and neck xenografts, 64 Cu-ATSM but not 64 CuCl 2 reflected pO 2 measurements, indicating that 64 Cu-ATSM is a hypoxia-specific marker in this tumor type. However, data from colorectal cancer xenografts indicated that 64 Cu-ATSM may not be a hypoxia marker in all tumor types.

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“…Whole-tumor montage images were obtained by acquiring multiple fields at 40· magnification, followed by alignment using MicroSuite Biologic Suite (version 2.7; Olympus). IHC and autoradiographic images were registered using Adobe Photoshop (CS6) as previously described (28).…”

Section: Autoradiography and Histologymentioning

confidence: 99%

⁸⁹Zr-DFO-AMG102 Immuno-PET to Determine Local Hepatocyte Growth Factor Protein Levels in Tumors for Enhanced Patient Selection

et al. 2017

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The hepatocyte growth factor (HGF) binding antibody rilotumumab (AMG102) was modified for use as a 89 Zr-based immuno-PET imaging agent to noninvasively determine the local levels of HGF protein in tumors. Because recent clinical trials of HGF-targeting therapies have been largely unsuccessful in several different cancers (e.g., gastric, brain, lung), we have synthesized and validated 89 Zr-DFO-AMG102 as a companion diagnostic for improved identification and selection of patients having high local levels of HGF in tumors. To date, patient selection has not been performed using the local levels of HGF protein in tumors. Methods: The chelator p-SCN-Bn-DFO was conjugated to AMG102, radiolabeling with 89 Zr was performed in high radiochemical yields and purity (.99%), and binding affinity of the modified antibody was confirmed using an enzyme-linked immunosorbent assay (ELISA)-type binding assay. PET imaging, biodistribution, autoradiography and immunohistochemistry, and ex vivo HGF ELISA experiments were performed on murine xenografts of U87MG (HGF-positive, MET-positive) and MKN45 (HGF-negative, MET-positive) and 4 patient-derived xenografts (MET-positive, HGF unknown). Results: Tumor uptake of 89 Zr-DFO-AMG102 at 120 h after injection in U87MG xenografts (HGF-positive) was high (36.8 6 7.8 percentage injected dose per gram [%ID/g]), whereas uptake in MKN45 xenografts (HGF-negative) was 5.0 6 1.3 %ID/g and a control of nonspecific human IgG 89 Zr-DFO-IgG in U87MG tumors was 11.5 6 3.3 %ID/g, demonstrating selective uptake in HGF-positive tumors. Similar experiments performed in 4 different gastric cancer patient-derived xenograft models showed low uptake of 89 Zr-DFO-AMG102 (;4-7 %ID/g), which corresponded with low HGF levels in these tumors (ex vivo ELISA). Autoradiography, immunohistochemical staining, and HGF ELISA assays confirmed that elevated levels of HGF protein were present only in U87MG tumors and that 89 Zr-DFO-AMG102 uptake was closely correlated with HGF protein levels in tumors. Conclusion: The new immuno-PET imaging agent 89 Zr-DFO-AMG102 was successfully synthesized, radiolabeled, and validated in vitro and in vivo to selectively accumulate in tumors with high local levels of HGF protein. These results suggest that 89 Zr-DFO-AMG102 would be a valuable companion diagnostic tool for the noninvasive selection of patients with elevated local concentrations of HGF in tumors for planning any HGF-targeted therapy, with the potential to improve clinical outcomes.

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A Comparison of the Imaging Characteristics and Microregional Distribution of 4 Hypoxia PET Tracers

Cited by 109 publications

References 32 publications

A limited overlap between intratumoral distribution of 1-(5-fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole and copper-diacetyl-bis[N(4)-methylthiosemicarbazone]

A limited overlap between intratumoral distribution of 1-(5-fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole and copper-diacetyl-bis[N(4)-methylthiosemicarbazone]

⁶⁴Cu-ATSM Reflects pO₂ Levels in Human Head and Neck Cancer Xenografts but Not in Colorectal Cancer Xenografts: Comparison with ⁶⁴CuCl₂

⁸⁹Zr-DFO-AMG102 Immuno-PET to Determine Local Hepatocyte Growth Factor Protein Levels in Tumors for Enhanced Patient Selection

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A Comparison of the Imaging Characteristics and Microregional Distribution of 4 Hypoxia PET Tracers

Cited by 109 publications

References 32 publications

A limited overlap between intratumoral distribution of 1-(5-fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole and copper-diacetyl-bis[N(4)-methylthiosemicarbazone]

A limited overlap between intratumoral distribution of 1-(5-fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole and copper-diacetyl-bis[N(4)-methylthiosemicarbazone]

64Cu-ATSM Reflects pO2 Levels in Human Head and Neck Cancer Xenografts but Not in Colorectal Cancer Xenografts: Comparison with 64CuCl2

89Zr-DFO-AMG102 Immuno-PET to Determine Local Hepatocyte Growth Factor Protein Levels in Tumors for Enhanced Patient Selection

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Product

Resources

About

⁶⁴Cu-ATSM Reflects pO₂ Levels in Human Head and Neck Cancer Xenografts but Not in Colorectal Cancer Xenografts: Comparison with ⁶⁴CuCl₂

⁸⁹Zr-DFO-AMG102 Immuno-PET to Determine Local Hepatocyte Growth Factor Protein Levels in Tumors for Enhanced Patient Selection