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Bodalal Z, Bogveradze N, Ter Beek LC, van den Berg JG, Sanders J, Hofland I, Trebeschi S, Groot Lipman KBW, Storck K, Hong EK, Lebedyeva N, Maas M, Beets-Tan RGH, Gomez FM, Kurilova I. Radiomic signatures from T2W and DWI MRI are predictive of tumour hypoxia in colorectal liver metastases. Insights Imaging 2023; 14:133. [PMID: 37477715 PMCID: PMC10361926 DOI: 10.1186/s13244-023-01474-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 06/27/2023] [Indexed: 07/22/2023] Open
Abstract
BACKGROUND Tumour hypoxia is a negative predictive and prognostic biomarker in colorectal cancer typically assessed by invasive sampling methods, which suffer from many shortcomings. This retrospective proof-of-principle study explores the potential of MRI-derived imaging markers in predicting tumour hypoxia non-invasively in patients with colorectal liver metastases (CLM). METHODS A single-centre cohort of 146 CLMs from 112 patients were segmented on preoperative T2-weighted (T2W) images and diffusion-weighted imaging (DWI). HIF-1 alpha immunohistochemical staining index (high/low) was used as a reference standard. Radiomic features were extracted, and machine learning approaches were implemented to predict the degree of histopathological tumour hypoxia. RESULTS Radiomic signatures from DWI b200 (AUC = 0.79, 95% CI 0.61-0.93, p = 0.002) and ADC (AUC = 0.72, 95% CI 0.50-0.90, p = 0.019) were significantly predictive of tumour hypoxia. Morphological T2W TE75 (AUC = 0.64, 95% CI 0.42-0.82, p = 0.092) and functional DWI b0 (AUC = 0.66, 95% CI 0.46-0.84, p = 0.069) and b800 (AUC = 0.64, 95% CI 0.44-0.82, p = 0.071) images also provided predictive information. T2W TE300 (AUC = 0.57, 95% CI 0.33-0.78, p = 0.312) and b = 10 (AUC = 0.53, 95% CI 0.33-0.74, p = 0.415) images were not predictive of tumour hypoxia. CONCLUSIONS T2W and DWI sequences encode information predictive of tumour hypoxia. Prospective multicentre studies could help develop and validate robust non-invasive hypoxia-detection algorithms. CRITICAL RELEVANCE STATEMENT Hypoxia is a negative prognostic biomarker in colorectal cancer. Hypoxia is usually assessed by invasive sampling methods. This proof-of-principle retrospective study explores the role of AI-based MRI-derived imaging biomarkers in non-invasively predicting tumour hypoxia in patients with colorectal liver metastases (CLM).
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Affiliation(s)
- Zuhir Bodalal
- Department of Radiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Nino Bogveradze
- Department of Radiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
- Department of Radiology, American Hospital Tbilisi, Tbilisi, Georgia
| | - Leon C Ter Beek
- Department of Medical Physics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jose G van den Berg
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Joyce Sanders
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ingrid Hofland
- Core Facility Molecular Pathology & Biobank, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Stefano Trebeschi
- Department of Radiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Kevin B W Groot Lipman
- Department of Radiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Koen Storck
- Department of Radiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Eun Kyoung Hong
- Department of Radiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Natalya Lebedyeva
- Department of Radiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Monique Maas
- Department of Radiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Regina G H Beets-Tan
- Department of Radiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Fernando M Gomez
- Department of Radiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
- Hospital Clinic-Hospital Sant Joan de Deu, Barcelona, Spain.
| | - Ieva Kurilova
- Department of Radiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
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Tamaki N, Hirata K, Kotani T, Nakai Y, Matsushima S, Yamada K. Four-dimensional quantitative analysis using FDG-PET in clinical oncology. Jpn J Radiol 2023:10.1007/s11604-023-01411-4. [PMID: 36947283 PMCID: PMC10366296 DOI: 10.1007/s11604-023-01411-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 03/02/2023] [Indexed: 03/23/2023]
Abstract
Positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) has been commonly used in many oncological areas. High-resolution PET permits a three-dimensional analysis of FDG distributions on various lesions in vivo, which can be applied for tissue characterization, risk analysis, and treatment monitoring after chemoradiotherapy and immunotherapy. Metabolic changes can be assessed using the tumor absolute FDG uptake as standardized uptake value (SUV) and metabolic tumor volume (MTV). In addition, tumor heterogeneity assessment can potentially estimate tumor aggressiveness and resistance to chemoradiotherapy. Attempts have been made to quantify intratumoral heterogeneity using radiomics. Recent reports have indicated the clinical feasibility of a dynamic FDG PET-computed tomography (CT) in pilot cohort studies of oncological cases. Dynamic imaging permits the assessment of temporal changes in FDG uptake after administration, which is particularly useful for differentiating pathological from physiological uptakes with high diagnostic accuracy. In addition, several new parameters have been introduced for the in vivo quantitative analysis of FDG metabolic processes. Thus, a four-dimensional FDG PET-CT is available for precise tissue characterization of various lesions. This review introduces various new techniques for the quantitative analysis of FDG distribution and glucose metabolism using a four-dimensional FDG analysis with PET-CT. This elegant study reveals the important role of tissue characterization and treatment strategies in oncology.
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Affiliation(s)
- Nagara Tamaki
- Department of Radiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Kenji Hirata
- Department of Diagnostic Imaging, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Tomoya Kotani
- Department of Radiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshitomo Nakai
- Department of Radiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shigenori Matsushima
- Department of Radiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kei Yamada
- Department of Radiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Zhu J, Pan F, Cai H, Pan L, Li Y, Li L, Li Y, Wu X, Fan H. Positron emission tomography imaging of lung cancer: An overview of alternative positron emission tomography tracers beyond F18 fluorodeoxyglucose. Front Med (Lausanne) 2022; 9:945602. [PMID: 36275809 PMCID: PMC9581209 DOI: 10.3389/fmed.2022.945602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/31/2022] [Indexed: 11/13/2022] Open
Abstract
Lung cancer has been the leading cause of cancer-related mortality in China in recent decades. Positron emission tomography-computer tomography (PET/CT) has been established in the diagnosis of lung cancer. 18F-FDG is the most widely used PET tracer in foci diagnosis, tumor staging, treatment planning, and prognosis assessment by monitoring abnormally exuberant glucose metabolism in tumors. However, with the increasing knowledge on tumor heterogeneity and biological characteristics in lung cancer, a variety of novel radiotracers beyond 18F-FDG for PET imaging have been developed. For example, PET tracers that target cellular proliferation, amino acid metabolism and transportation, tumor hypoxia, angiogenesis, pulmonary NETs and other targets, such as tyrosine kinases and cancer-associated fibroblasts, have been reported, evaluated in animal models or under clinical investigations in recent years and play increasing roles in lung cancer diagnosis. Thus, we perform a comprehensive literature review of the radiopharmaceuticals and recent progress in PET tracers for the study of lung cancer biological characteristics beyond glucose metabolism.
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Affiliation(s)
- Jing Zhu
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China,Respiratory and Critical Care Medicine, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China,NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Fei Pan
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Huawei Cai
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Lili Pan
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yalun Li
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Lin Li
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - YunChun Li
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China,Department of Nuclear Medicine, The Second People’s Hospital of Yibin, Yibin, China
| | - Xiaoai Wu
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China,Xiaoai Wu,
| | - Hong Fan
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Hong Fan,
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Xie F, Wei W. [ 64Cu]Cu-ATSM: an emerging theranostic agent for cancer and neuroinflammation. Eur J Nucl Med Mol Imaging 2022; 49:3964-3972. [PMID: 35918492 DOI: 10.1007/s00259-022-05887-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- Fang Xie
- PET Center, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Weijun Wei
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, 200127, China.
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Gallez B. The Role of Imaging Biomarkers to Guide Pharmacological Interventions Targeting Tumor Hypoxia. Front Pharmacol 2022; 13:853568. [PMID: 35910347 PMCID: PMC9335493 DOI: 10.3389/fphar.2022.853568] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 06/23/2022] [Indexed: 12/12/2022] Open
Abstract
Hypoxia is a common feature of solid tumors that contributes to angiogenesis, invasiveness, metastasis, altered metabolism and genomic instability. As hypoxia is a major actor in tumor progression and resistance to radiotherapy, chemotherapy and immunotherapy, multiple approaches have emerged to target tumor hypoxia. It includes among others pharmacological interventions designed to alleviate tumor hypoxia at the time of radiation therapy, prodrugs that are selectively activated in hypoxic cells or inhibitors of molecular targets involved in hypoxic cell survival (i.e., hypoxia inducible factors HIFs, PI3K/AKT/mTOR pathway, unfolded protein response). While numerous strategies were successful in pre-clinical models, their translation in the clinical practice has been disappointing so far. This therapeutic failure often results from the absence of appropriate stratification of patients that could benefit from targeted interventions. Companion diagnostics may help at different levels of the research and development, and in matching a patient to a specific intervention targeting hypoxia. In this review, we discuss the relative merits of the existing hypoxia biomarkers, their current status and the challenges for their future validation as companion diagnostics adapted to the nature of the intervention.
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Affiliation(s)
- Bernard Gallez
- Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université Catholique de Louvain (UCLouvain), Brussels, Belgium
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Chia K, Paul RL, Weeks AJ, Naeem M, Mullen GE, Landau D, Blower PJ. Correlation of hypoxia PET tracer uptake with hypoxic radioresistance in cancer cells: PET biomarkers of resistance to stereotactic radiation therapy? Nucl Med Biol 2022; 110-111:10-17. [DOI: 10.1016/j.nucmedbio.2022.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/24/2022] [Accepted: 04/06/2022] [Indexed: 11/16/2022]
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Earley DF, Esteban Flores J, Guillou A, Holland JP. Photoactivatable bis(thiosemicarbazone) derivatives for copper-64 radiotracer synthesis. Dalton Trans 2022; 51:5041-5052. [PMID: 35285835 PMCID: PMC8962981 DOI: 10.1039/d2dt00209d] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
In recent years, copper-64 and copper-67 have been considered as a useful theranostic pair in nuclear medicine, due to their favourable and complementary decay properties. As 67Cu and 64Cu are chemically identical, development of both existing and new bifunctional chelators for 64Cu imaging agents can be readily adapted for the 67Cu-radionuclide. In this study, we explored the use of photoactivatable copper chelators based on the asymmetric bis(thiosemicarbazone) scaffold, H2ATSM/en, for the photoradiolabelling of protein. Photoactivatable 64CuATSM-derivatives were prepared by both direct synthesis and transmetallation from the corresponding natZn complex. Then, irradiation with UV light in the presence of a protein of interest in a pH buffered aqueous solution afforded the 64Cu-labelled protein conjugates in decay-corrected radiochemical yield of 86.9 ± 1.0% via the transmetallation method and 35.3 ± 1.7% from the direct radiolabelling method. This study successfully demonstrates the viability of photochemically induced conjugation methods for the development of copper-based radiotracers for potential applications in diagnostic positron emission tomography (PET) imaging and targeted radionuclide therapy. In recent years, copper-64 and copper-67 have been considered as a useful theranostic pair in nuclear medicine. Here, we report a photochemically-mediated approach for radiolabelling biologically relevant protein with copper radionuclides.![]()
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Affiliation(s)
- Daniel F Earley
- Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
| | - Jose Esteban Flores
- Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
| | - Amaury Guillou
- Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
| | - Jason P Holland
- Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
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Nachankar A, Oike T, Hanaoka H, Kanai A, Sato H, Yoshida Y, Obinata H, Sakai M, Osu N, Hirota Y, Takahashi A, Shibata A, Ohno T. 64Cu-ATSM Predicts Efficacy of Carbon Ion Radiotherapy Associated with Cellular Antioxidant Capacity. Cancers (Basel) 2021; 13:cancers13246159. [PMID: 34944777 PMCID: PMC8699283 DOI: 10.3390/cancers13246159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/13/2021] [Accepted: 12/03/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Carbon ion radiotherapy is an emerging cancer treatment modality that has a greater therapeutic window than conventional photon radiotherapy. To maximize the efficacy of this extremely scarce medical resource, it is important to identify predictive biomarkers of higher carbon ion relative biological effectiveness (RBE) over photons. Here we show that the carbon ion RBE in human cancer cells correlates with the cellular uptake of 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. High RBE/64Cu-ATSM cells show greater steady-state levels of antioxidant proteins and increased capacity to scavenge reactive oxygen species in response to X-rays than low RBE/64Cu-ATSM counterparts. These data suggest that the cellular antioxidant activity is a possible determinant of carbon ion RBE predictable by 64Cu-ATSM uptake. Abstract Carbon ion radiotherapy is an emerging cancer treatment modality that has a greater therapeutic window than conventional photon radiotherapy. To maximize the efficacy of this extremely scarce medical resource, it is important to identify predictive biomarkers of higher carbon ion relative biological effectiveness (RBE) over photons. We addressed this issue by focusing on cellular antioxidant capacity and investigated 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. We found that the carbon ion RBE correlated with 64Cu-ATSM uptake both in vitro and in vivo. High RBE/64Cu-ATSM cells showed greater steady-state levels of antioxidant proteins and increased capacity to scavenge reactive oxygen species in response to X-rays than low RBE/64Cu-ATSM counterparts; this upregulation of antioxidant systems was associated with downregulation of TCA cycle intermediates. Furthermore, inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) sensitized high RBE/64Cu-ATSM cells to X-rays, thereby reducing RBE values to levels comparable to those in low RBE/64Cu-ATSM cells. These data suggest that the cellular activity of Nrf2-driven antioxidant systems is a possible determinant of carbon ion RBE predictable by 64Cu-ATSM uptake. These new findings highlight the potential clinical utility of 64Cu-ATSM imaging to identify high RBE tumors that will benefit from carbon ion radiotherapy.
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Affiliation(s)
- Ankita Nachankar
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (A.N.); (H.S.); (N.O.); (Y.H.); (T.O.)
| | - Takahiro Oike
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (A.N.); (H.S.); (N.O.); (Y.H.); (T.O.)
- Gunma University Heavy Ion Medical Center, Maebashi 371-8511, Japan; (Y.Y.); (M.S.); (A.T.)
- Correspondence: ; Tel.: +81-27-220-8383
| | - Hirofumi Hanaoka
- Department of Radiotheranostics, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (H.H.); (A.K.)
| | - Ayaka Kanai
- Department of Radiotheranostics, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (H.H.); (A.K.)
| | - Hiro Sato
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (A.N.); (H.S.); (N.O.); (Y.H.); (T.O.)
- Gunma University Heavy Ion Medical Center, Maebashi 371-8511, Japan; (Y.Y.); (M.S.); (A.T.)
| | - Yukari Yoshida
- Gunma University Heavy Ion Medical Center, Maebashi 371-8511, Japan; (Y.Y.); (M.S.); (A.T.)
| | - Hideru Obinata
- Laboratory for Analytical Instruments, Education and Research Support Center, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan;
| | - Makoto Sakai
- Gunma University Heavy Ion Medical Center, Maebashi 371-8511, Japan; (Y.Y.); (M.S.); (A.T.)
| | - Naoto Osu
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (A.N.); (H.S.); (N.O.); (Y.H.); (T.O.)
| | - Yuka Hirota
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (A.N.); (H.S.); (N.O.); (Y.H.); (T.O.)
| | - Akihisa Takahashi
- Gunma University Heavy Ion Medical Center, Maebashi 371-8511, Japan; (Y.Y.); (M.S.); (A.T.)
| | - Atsushi Shibata
- Signal Transduction Program, Gunma University Initiative for Advanced Research (GIAR), Maebashi 371-8511, Japan;
| | - Tatsuya Ohno
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (A.N.); (H.S.); (N.O.); (Y.H.); (T.O.)
- Gunma University Heavy Ion Medical Center, Maebashi 371-8511, Japan; (Y.Y.); (M.S.); (A.T.)
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D'Alonzo RA, Gill S, Rowshanfarzad P, Keam S, MacKinnon KM, Cook AM, Ebert MA. In vivo noninvasive preclinical tumor hypoxia imaging methods: a review. Int J Radiat Biol 2021; 97:593-631. [PMID: 33703994 DOI: 10.1080/09553002.2021.1900943] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 01/28/2021] [Accepted: 03/01/2021] [Indexed: 12/15/2022]
Abstract
Tumors exhibit areas of decreased oxygenation due to malformed blood vessels. This low oxygen concentration decreases the effectiveness of radiation therapy, and the resulting poor perfusion can prevent drugs from reaching areas of the tumor. Tumor hypoxia is associated with poorer prognosis and disease progression, and is therefore of interest to preclinical researchers. Although there are multiple different ways to measure tumor hypoxia and related factors, there is no standard for quantifying spatial and temporal tumor hypoxia distributions in preclinical research or in the clinic. This review compares imaging methods utilized for the purpose of assessing spatio-temporal patterns of hypoxia in the preclinical setting. Imaging methods provide varying levels of spatial and temporal resolution regarding different aspects of hypoxia, and with varying advantages and disadvantages. The choice of modality requires consideration of the specific experimental model, the nature of the required characterization and the availability of complementary modalities as well as immunohistochemistry.
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Affiliation(s)
- Rebecca A D'Alonzo
- School of Physics, Mathematics and Computing, The University of Western Australia, Crawley, Australia
| | - Suki Gill
- School of Physics, Mathematics and Computing, The University of Western Australia, Crawley, Australia
- Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Australia
| | - Pejman Rowshanfarzad
- School of Physics, Mathematics and Computing, The University of Western Australia, Crawley, Australia
| | - Synat Keam
- School of Medicine, The University of Western Australia, Crawley, Australia
| | - Kelly M MacKinnon
- School of Physics, Mathematics and Computing, The University of Western Australia, Crawley, Australia
| | - Alistair M Cook
- School of Medicine, The University of Western Australia, Crawley, Australia
| | - Martin A Ebert
- School of Physics, Mathematics and Computing, The University of Western Australia, Crawley, Australia
- Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Australia
- 5D Clinics, Claremont, Australia
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Imaging Hypoxia. Mol Imaging 2021. [DOI: 10.1016/b978-0-12-816386-3.00074-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Busk M, Overgaard J, Horsman MR. Imaging of Tumor Hypoxia for Radiotherapy: Current Status and Future Directions. Semin Nucl Med 2020; 50:562-583. [PMID: 33059825 DOI: 10.1053/j.semnuclmed.2020.05.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Tumor regions that are transiently or chronically undersupplied with oxygen (hypoxia) and nutrients, and enriched with acidic waste products, are common due to an abnormal and inefficient tumor vasculature, and a deviant highly glycolytic energy metabolism. There is compelling evidence that tumor hypoxia is strongly linked to poor prognosis since oxygen-deprived cells are highly resistant to therapy including radio- and chemotherapy, and survival of such cells is a primary cause of disease relapse. Despite a general improvement in cancer survival rates, hypoxia remains a formidable challenge. Recent progress in radiation delivery systems with improved spatial accuracy that allows dose escalation to hypoxic tumors or even tumor subvolumes, and the development of hypoxia-selective drugs, including bioreductive prodrugs, holds great promise for overcoming this obstacle. However, apart from one notable exception, translation of promising preclinical therapies to the clinic have largely been disappointing. A major obstacle in clinical trials on hypoxia-targeting strategies has been the lack of reliable information on tumor hypoxia, which is crucial for patient stratification into groups of those that are likely to benefit from intervention and those who are not. Further, in many newer trials on hypoxia-selective drugs the choice of cancer disease and combination therapy has not always been ideal, especially not for clinical proof of principle trials. Clearly, there is a pending need for clinical applicable methodologies that may allow us to quantify, map and monitor hypoxia. Molecular imaging may provide the information required for narrowing the gap between potential and actual patient benefit of hypoxia-targeting strategies. The grand majority of preclinical and clinical work has focused on the usefulness of PET-based assessment of hypoxia-selective tracers. Since hypoxia PET has profound inherent weaknesses, the use of other methodologies, including more indirect methods that quantifies blood flow or oxygenation-dependent flux changes through ATP-generating pathways (eg, anaerobic glycolysis) is being extensively studied. In this review, we briefly discuss established and emerging hypoxia-targeting strategies, followed by a more thorough evaluation of strengths and weaknesses of clinical applicable imaging methodologies that may guide timely treatment intensification to overcome hypoxia-driven resistance. Historically, most evidence for the linkage between hypoxia and poor outcome is based on work in the field of radiotherapy. Therefore, main emphasis in this review is on targeting and imaging of hypoxia for improved radiotherapy.
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Affiliation(s)
- Morten Busk
- Experimental Clinical Oncology, Department of Oncology, Aarhus University Hospital (AUH), Aarhus, Denmark; Danish Centre for Particle Therapy, (AUH), Aarhus, Denmark.
| | - Jens Overgaard
- Experimental Clinical Oncology, Department of Oncology, Aarhus University Hospital (AUH), Aarhus, Denmark
| | - Michael R Horsman
- Experimental Clinical Oncology, Department of Oncology, Aarhus University Hospital (AUH), Aarhus, Denmark
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Waller J, Onderdonk B, Flood A, Swartz H, Shah J, Shah A, Aydogan B, Halpern H, Hasan Y. The clinical utility of imaging methods used to measure hypoxia in cervical cancer. Br J Radiol 2020; 93:20190640. [PMID: 32286849 PMCID: PMC7336054 DOI: 10.1259/bjr.20190640] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 03/18/2020] [Accepted: 04/07/2020] [Indexed: 12/13/2022] Open
Abstract
While it is well-established that hypoxia is a major factor that affects clinical outcomes in cervical cancer, widespread usage of clinically available methods to detect and evaluate hypoxia during the course of treatment have not been established. This review compares these methods, summarizes their strengths and weaknesses, and assesses the pathways for their useful employment to alter clinical practice. We conducted a search on PubMed for literature pertaining to imaging hypoxic cervical cancer, and implemented keywords related to oxygen measurement tools to improve the relevance of the search results.Oxygenation level-dependent applications of MRI have demonstrated hypoxia-induced radioresistance, and changes in cervix tumor oxygenation from hyperoxic therapy.The hypoxic areas within tumors can be indirectly identified in dynamic contrast-enhanced images, where they generally display low signal enhancement, and diffusion-weighted images, which demonstrates areas of restricted diffusion (which correlates with hypoxia). Positron emmision tomography, used independently and with other imaging modalities, has demonstrated utility in imaging hypoxia through tracers specific for low oxygen levels, like Cu-ATSM tracers and nitroimidazoles. Detecting hypoxia in the tumors of patients diagnosed with cervical cancer via medical imaging and non-imaging tools like electron paramagnetic resonance oximetry can be utilized clinically, such as for guiding radiation and post-treatment surveillance, for a more personalized approach to treatment. The merits of these methods warrant further investigation via comparative effectiveness research and large clinical trials into their clinical applications.
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Affiliation(s)
- Joseph Waller
- Drexel College of Medicine, 2900 W Queen Ln, PA 19129, United States
| | - Benjamin Onderdonk
- Department of Radiation and Cellular Oncology, The University of Chicago, 5758 S Maryland Ave, IL 60637, United States
| | - Ann Flood
- Department of Radiology, Dartmouth Geisel School of Medicine, 1 Rope Ferry Rd, NH 03755, United States
| | - Harold Swartz
- Department of Radiology, Dartmouth Geisel School of Medicine, 1 Rope Ferry Rd, NH 03755, United States
| | - Jaffer Shah
- Drexel College of Medicine, 2900 W Queen Ln, PA 19129, United States
| | - Asghar Shah
- Brown University, Providence, RI 02912, United States
| | - Bulent Aydogan
- Department of Radiation and Cellular Oncology, The University of Chicago, 5758 S Maryland Ave, IL 60637, United States
| | - Howard Halpern
- Department of Radiation and Cellular Oncology, The University of Chicago, 5758 S Maryland Ave, IL 60637, United States
| | - Yasmin Hasan
- Department of Radiation and Cellular Oncology, The University of Chicago, 5758 S Maryland Ave, IL 60637, United States
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Sanduleanu S, van der Wiel AM, Lieverse RI, Marcus D, Ibrahim A, Primakov S, Wu G, Theys J, Yaromina A, Dubois LJ, Lambin P. Hypoxia PET Imaging with [18F]-HX4-A Promising Next-Generation Tracer. Cancers (Basel) 2020; 12:cancers12051322. [PMID: 32455922 PMCID: PMC7280995 DOI: 10.3390/cancers12051322] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/18/2020] [Accepted: 05/19/2020] [Indexed: 02/04/2023] Open
Abstract
Hypoxia—a common feature of the majority of solid tumors—is a negative prognostic factor, as it is associated with invasion, metastasis and therapy resistance. To date, a variety of methods are available for the assessment of tumor hypoxia, including the use of positron emission tomography (PET). A plethora of hypoxia PET tracers, each with its own strengths and limitations, has been developed and successfully validated, thereby providing useful prognostic or predictive information. The current review focusses on [18F]-HX4, a promising next-generation hypoxia PET tracer. After a brief history of its development, we discuss and compare its characteristics with other hypoxia PET tracers and provide an update on its progression into the clinic. Lastly, we address the potential applications of assessing tumor hypoxia using [18F]-HX4, with a focus on improving patient-tailored therapies.
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Affiliation(s)
- Sebastian Sanduleanu
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW—School for Oncology, Maastricht University, 6211 Maastricht, The Netherlands; (A.M.A.v.d.W.); (R.I.Y.L.); (D.M.); (A.I.); (S.P.); (G.W.); (J.T.); (A.Y.); (L.J.D.); (P.L.)
- Correspondence:
| | - Alexander M.A. van der Wiel
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW—School for Oncology, Maastricht University, 6211 Maastricht, The Netherlands; (A.M.A.v.d.W.); (R.I.Y.L.); (D.M.); (A.I.); (S.P.); (G.W.); (J.T.); (A.Y.); (L.J.D.); (P.L.)
| | - Relinde I.Y. Lieverse
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW—School for Oncology, Maastricht University, 6211 Maastricht, The Netherlands; (A.M.A.v.d.W.); (R.I.Y.L.); (D.M.); (A.I.); (S.P.); (G.W.); (J.T.); (A.Y.); (L.J.D.); (P.L.)
| | - Damiënne Marcus
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW—School for Oncology, Maastricht University, 6211 Maastricht, The Netherlands; (A.M.A.v.d.W.); (R.I.Y.L.); (D.M.); (A.I.); (S.P.); (G.W.); (J.T.); (A.Y.); (L.J.D.); (P.L.)
| | - Abdalla Ibrahim
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW—School for Oncology, Maastricht University, 6211 Maastricht, The Netherlands; (A.M.A.v.d.W.); (R.I.Y.L.); (D.M.); (A.I.); (S.P.); (G.W.); (J.T.); (A.Y.); (L.J.D.); (P.L.)
- Department of Radiology and Nuclear Medicine, GROW—School for Oncology and Developmental Biology, Maastricht University Medical Centre+, 6229 Maastricht, The Netherlands
- Division of Nuclear Medicine and Oncological Imaging, Department of Medical Physics, Hospital Center Universitaire De Liege, 4030 Liege, Belgium
- Department of Nuclear Medicine and Comprehensive Diagnostic Center Aachen (CDCA), University Hospital RWTH Aachen University, 52074 Aachen, Germany
| | - Sergey Primakov
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW—School for Oncology, Maastricht University, 6211 Maastricht, The Netherlands; (A.M.A.v.d.W.); (R.I.Y.L.); (D.M.); (A.I.); (S.P.); (G.W.); (J.T.); (A.Y.); (L.J.D.); (P.L.)
| | - Guangyao Wu
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW—School for Oncology, Maastricht University, 6211 Maastricht, The Netherlands; (A.M.A.v.d.W.); (R.I.Y.L.); (D.M.); (A.I.); (S.P.); (G.W.); (J.T.); (A.Y.); (L.J.D.); (P.L.)
| | - Jan Theys
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW—School for Oncology, Maastricht University, 6211 Maastricht, The Netherlands; (A.M.A.v.d.W.); (R.I.Y.L.); (D.M.); (A.I.); (S.P.); (G.W.); (J.T.); (A.Y.); (L.J.D.); (P.L.)
| | - Ala Yaromina
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW—School for Oncology, Maastricht University, 6211 Maastricht, The Netherlands; (A.M.A.v.d.W.); (R.I.Y.L.); (D.M.); (A.I.); (S.P.); (G.W.); (J.T.); (A.Y.); (L.J.D.); (P.L.)
| | - Ludwig J. Dubois
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW—School for Oncology, Maastricht University, 6211 Maastricht, The Netherlands; (A.M.A.v.d.W.); (R.I.Y.L.); (D.M.); (A.I.); (S.P.); (G.W.); (J.T.); (A.Y.); (L.J.D.); (P.L.)
| | - Philippe Lambin
- The D-Lab and The M-Lab, Department of Precision Medicine, GROW—School for Oncology, Maastricht University, 6211 Maastricht, The Netherlands; (A.M.A.v.d.W.); (R.I.Y.L.); (D.M.); (A.I.); (S.P.); (G.W.); (J.T.); (A.Y.); (L.J.D.); (P.L.)
- Department of Radiology and Nuclear Medicine, GROW—School for Oncology and Developmental Biology, Maastricht University Medical Centre+, 6229 Maastricht, The Netherlands
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Ron A, Deán-Ben XL, Gottschalk S, Razansky D. Volumetric Optoacoustic Imaging Unveils High-Resolution Patterns of Acute and Cyclic Hypoxia in a Murine Model of Breast Cancer. Cancer Res 2019; 79:4767-4775. [PMID: 31097477 DOI: 10.1158/0008-5472.can-18-3769] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 04/03/2019] [Accepted: 05/10/2019] [Indexed: 11/16/2022]
Abstract
Mapping tumor heterogeneity and hypoxia within a living intact organism is essential for understanding the processes involved in cancer progression and assessing long-term responses to therapies. Efficient investigations into tumor hypoxia mechanisms have been hindered by the lack of intravital imaging tools capable of multiparametric probing of entire solid tumors with high spatial and temporal resolution. Here, we exploit volumetric multispectral optoacoustic tomography (vMSOT) for accurate, label-free delineation of tumor heterogeneity and dynamic oxygenation behavior. Mice bearing orthotopic MDA-MB-231 breast cancer xenografts were imaged noninvasively during rest and oxygen stress challenge, attaining time-lapse three-dimensional oxygenation maps across entire tumors with 100 μm spatial resolution. Volumetric quantification of the hypoxic fraction rendered values of 3.9% to 21.2%, whereas the oxygen saturation (sO2) rate declined at 1.7% to 2.3% per mm in all tumors when approaching their core. Three distinct functional areas (the rim, hypoxic, and normoxic cores) were clearly discernible based on spatial sO2 profiles and responses to oxygen challenge. Notably, although sO2 readings were responsive to the challenge, deoxyhemoglobin (HbR) trends exhibited little to no variations in all mice. Dynamic analysis further revealed the presence of cyclic hypoxia patterns with a 21% average discrepancy between cyclic fractions assessed via sO2 (42.2% ± 17.3%) and HbR fluctuations (63% ± 14.1%) within the hypoxic core. These findings corroborate the strong potential of vMSOT for advancing preclinical imaging of cancer and informing clinical decisions on therapeutic interventions. SIGNIFICANCE: vMSOT provides quantitative measures of volumetric hypoxic fraction and cyclic hypoxia in a label-free and noninvasive manner, providing new readouts to aid tumor staging and treatment decision making. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/18/4767/F1.large.jpg.See related commentary by Klibanov and Hu, p. 4577.
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Affiliation(s)
- Avihai Ron
- Institute for Biological and Medical Imaging, Helmholtz Center Munich, Neuherberg, Germany.,Faculty of Medicine, Technical University of Munich, Munich, Germany
| | - Xosé Luís Deán-Ben
- Institute for Biological and Medical Imaging, Helmholtz Center Munich, Neuherberg, Germany.,Faculty of Medicine and Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.,Department of Information Technology and Electrical Engineering, Institute for Biomedical Engineering ETH Zurich, Zurich, Switzerland
| | - Sven Gottschalk
- Institute for Biological and Medical Imaging, Helmholtz Center Munich, Neuherberg, Germany
| | - Daniel Razansky
- Institute for Biological and Medical Imaging, Helmholtz Center Munich, Neuherberg, Germany. .,Faculty of Medicine, Technical University of Munich, Munich, Germany.,Faculty of Medicine and Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.,Department of Information Technology and Electrical Engineering, Institute for Biomedical Engineering ETH Zurich, Zurich, Switzerland
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15
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How to Modulate Tumor Hypoxia for Preclinical In Vivo Imaging Research. CONTRAST MEDIA & MOLECULAR IMAGING 2018; 2018:4608186. [PMID: 30420794 PMCID: PMC6211155 DOI: 10.1155/2018/4608186] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 07/24/2018] [Accepted: 08/13/2018] [Indexed: 01/20/2023]
Abstract
Tumor hypoxia is related with tumor aggressiveness, chemo- and radiotherapy resistance, and thus a poor clinical outcome. Therefore, over the past decades, every effort has been made to develop strategies to battle the negative prognostic influence of tumor hypoxia. For appropriate patient selection and follow-up, noninvasive imaging biomarkers such as positron emission tomography (PET) radiolabeled ligands are unprecedentedly needed. Importantly, before being able to implement these new therapies and potential biomarkers into the clinical setting, preclinical in vivo validation in adequate animal models is indispensable. In this review, we provide an overview of the different attempts that have been made to create differential hypoxic in vivo cancer models with a particular focus on their applicability in PET imaging studies.
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Bonnitcha P, Grieve S, Figtree G. Clinical imaging of hypoxia: Current status and future directions. Free Radic Biol Med 2018; 126:296-312. [PMID: 30130569 DOI: 10.1016/j.freeradbiomed.2018.08.019] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 07/30/2018] [Accepted: 08/14/2018] [Indexed: 12/20/2022]
Abstract
Tissue hypoxia is a key feature of many important causes of morbidity and mortality. In pathologies such as stroke, peripheral vascular disease and ischaemic heart disease, hypoxia is largely a consequence of low blood flow induced ischaemia, hence perfusion imaging is often used as a surrogate for hypoxia to guide clinical diagnosis and treatment. Importantly, ischaemia and hypoxia are not synonymous conditions as it is not universally true that well perfused tissues are normoxic or that poorly perfused tissues are hypoxic. In pathologies such as cancer, for instance, perfusion imaging and oxygen concentration are less well correlated, and oxygen concentration is independently correlated to radiotherapy response and overall treatment outcomes. In addition, the progression of many diseases is intricately related to maladaptive responses to the hypoxia itself. Thus there is potentially great clinical and scientific utility in direct measurements of tissue oxygenation. Despite this, imaging assessment of hypoxia in patients is rarely performed in clinical settings. This review summarises some of the current methods used to clinically evaluate hypoxia, the barriers to the routine use of these methods and the newer agents and techniques being explored for the assessment of hypoxia in pathological processes.
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Affiliation(s)
- Paul Bonnitcha
- Northern and Central Clinical Schools, Faculty of Medicine, Sydney University, Sydney, NSW 2006, Australia; Chemical Pathology Department, NSW Health Pathology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia; Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales 2065, Australia.
| | - Stuart Grieve
- Sydney Translational Imaging Laboratory, Heart Research Institute, Charles Perkins Centre and Sydney Medical School, University of Sydney, NSW 2050, Australia
| | - Gemma Figtree
- Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales 2065, Australia; Cardiology Department, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia
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17
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Toriihara A, Ohtake M, Tateishi K, Hino-Shishikura A, Yoneyama T, Kitazume Y, Inoue T, Kawahara N, Tateishi U. Prognostic implications of 62Cu-diacetyl-bis (N 4-methylthiosemicarbazone) PET/CT in patients with glioma. Ann Nucl Med 2018; 32:264-271. [PMID: 29453680 DOI: 10.1007/s12149-018-1241-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 02/13/2018] [Indexed: 11/29/2022]
Abstract
OBJECTIVE The potential of positron emission tomography/computed tomography using 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) (62Cu-ATSM PET/CT), which was originally developed as a hypoxic tracer, to predict therapeutic resistance and prognosis has been reported in various cancers. Our purpose was to investigate prognostic value of 62Cu-ATSM PET/CT in patients with glioma, compared to PET/CT using 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG). METHOD 56 patients with glioma of World Health Organization grade 2-4 were enrolled. All participants had undergone both 62Cu-ATSM PET/CT and 18F-FDG PET/CT within mean 33.5 days prior to treatment. Maximum standardized uptake value and tumor/background ratio were calculated within areas of increased radiotracer uptake. The prognostic significance for progression-free survival and overall survival were assessed by log-rank test and Cox's proportional hazards model. RESULTS Disease progression and death were confirmed in 37 and 27 patients in follow-up periods, respectively. In univariate analysis, there was significant difference of both progression-free survival and overall survival in age, tumor grade, history of chemoradiotherapy, maximum standardized uptake value and tumor/background ratio calculated using 62Cu-ATSM PET/CT. Multivariate analysis revealed that maximum standardized uptake value calculated using 62Cu-ATSM PET/CT was an independent predictor of both progression-free survival and overall survival (p < 0.05). In a subgroup analysis including patients of grade 4 glioma, only the maximum standardized uptake values calculated using 62Cu-ATSM PET/CT showed significant difference of progression-free survival (p < 0.05). CONCLUSIONS 62Cu-ATSM PET/CT is a more promising imaging method to predict prognosis of patients with glioma compared to 18F-FDG PET/CT.
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Affiliation(s)
- Akira Toriihara
- Department of Diagnostic Radiology and Nuclear Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Makoto Ohtake
- Departments of Neurosurgery, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Kensuke Tateishi
- Departments of Neurosurgery, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Ayako Hino-Shishikura
- Departments of Radiology, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Tomohiro Yoneyama
- Department of Diagnostic Radiology and Nuclear Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Yoshio Kitazume
- Department of Diagnostic Radiology and Nuclear Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Tomio Inoue
- Departments of Radiology, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Nobutaka Kawahara
- Departments of Neurosurgery, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Ukihide Tateishi
- Department of Diagnostic Radiology and Nuclear Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
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Thorwarth D, Wack LJ, Mönnich D. Hypoxia PET imaging techniques: data acquisition and analysis. Clin Transl Imaging 2017. [DOI: 10.1007/s40336-017-0250-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Challapalli A, Carroll L, Aboagye EO. Molecular mechanisms of hypoxia in cancer. Clin Transl Imaging 2017; 5:225-253. [PMID: 28596947 PMCID: PMC5437135 DOI: 10.1007/s40336-017-0231-1] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 04/21/2017] [Indexed: 02/07/2023]
Abstract
PURPOSE Hypoxia is a condition of insufficient oxygen to support metabolism which occurs when the vascular supply is interrupted, or when a tumour outgrows its vascular supply. It is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. This review provides an overview of hypoxia imaging with Positron emission tomography (PET), with an emphasis on the biological relevance, mechanism of action, highlighting advantages, and limitations of the currently available hypoxia radiotracers. METHODS A comprehensive PubMed literature search was performed, identifying articles relating to biological significance and measurement of hypoxia, MRI methods, and PET imaging of hypoxia in preclinical and clinical settings, up to December 2016. RESULTS A variety of approaches have been explored over the years for detecting and monitoring changes in tumour hypoxia, including regional measurements with oxygen electrodes placed under CT guidance, MRI methods that measure either oxygenation or lactate production consequent to hypoxia, different nuclear medicine approaches that utilise imaging agents the accumulation of which is inversely related to oxygen tension, and optical methods. The advantages and disadvantages of these approaches are reviewed, along with individual strategies for validating different imaging methods. PET is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. CONCLUSION Even though hypoxia could have significant prognostic and predictive value in the clinic, the best method for hypoxia assessment has in our opinion not been realised.
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Affiliation(s)
- Amarnath Challapalli
- Department of Clinical Oncology, Bristol Cancer Institute, Horfield Road, Bristol, United Kingdom
| | - Laurence Carroll
- Department of Surgery and Cancer, Imperial College, GN1, Commonwealth Building, Hammersmith Hospital, Du Cane Road, London, W120NN United Kingdom
| | - Eric O. Aboagye
- Department of Surgery and Cancer, Imperial College, GN1, Commonwealth Building, Hammersmith Hospital, Du Cane Road, London, W120NN United Kingdom
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Lopci E, Grizzi F, Russo C, Toschi L, Grassi I, Cicoria G, Lodi F, Mattioli S, Fanti S. Early and delayed evaluation of solid tumours with 64Cu-ATSM PET/CT: a pilot study on semiquantitative and computer-aided fractal geometry analysis. Nucl Med Commun 2017; 38:340-346. [PMID: 28263239 DOI: 10.1097/mnm.0000000000000656] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The aim of this study was to analyse early and delayed acquisition on copper-64 diacetyl-bisN4-methylthiosemicarbazone (Cu-ATSM) PET/CT in a small cohort of patients by comparing semiquantitative and computer-aided fractal geometry analyses. PATIENTS AND METHODS Five cancer patients, including non-small-cell lung cancer and head and neck cancer, were investigated with Cu-ATSM PET/CT. Participants received an intravenous injection of Cu-ATSM according to body size and were imaged 60 min (early) and 16 h (delayed) later on hybrid PET/CT. Reconstructed images were visualized on advanced workstations for the definition of semiquantitative parameters: standardized uptake value (SUV)max, SUVratio-to-muscle, SUVmean, hypoxic volume (HV) and hypoxic burden (HB=HV×SUVmean). DICOM data retrieved from both scans were analysed using an ad-hoc computer program to determine the mean intensity value, SD, relative dispersion, three-dimensional histogram fractal dimension and three-dimensional fractal dimension. RESULTS All tumour lesions showed increased uptake of Cu-ATSM at early evaluation, with a median SUVratio-to-muscle of 4.42 (range: 1.58-5.62), a median SUVmax of 5.3 (range: 1.9-7.3), a median SUVmean of 2.8 (range: 1.5-3.9), a median HV of 41.6 cm (range: 2.8-453.7) and a median HB of 161.5 cm (range: 4.4-1112.5). All semiquantitative data obtained at 1 h were consistent with the parameters obtained on delayed imaging (P>0.05). A borderline statistically significant difference was found only for SUVmax of the muscle (P=0.045). Fractal geometry analysis on DICOM images showed that all parameters at early imaging showed no statistically significant difference with late acquisition (P>0.05). CONCLUSION Our findings support the consistency of Cu-ATSM PET/CT images obtained at early and delayed acquisition for the assessment of tumour lesions.
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Affiliation(s)
- Egesta Lopci
- aResearch Doctorate Course in Specialized Medical Sciences, Alma Mater Studiorum - University of Bologna bPET Unit cDivision of Thoracic Surgery, University Hospital S. Orsola-Malpighi, Bologna dDepartment of Nuclear Medicine eDepartment of Inflammation and Immunology fDepartment of Medical Oncology, Humanitas Clinical and Research Hospital, Rozzano gMichele Rodriguez Foundation, Milan, Italy
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Palma E, Mendes F, Morais GR, Rodrigues I, Santos IC, Campello MPC, Raposinho P, Correia I, Gama S, Belo D, Alves V, Abrunhosa AJ, Santos I, Paulo A. Biophysical characterization and antineoplastic activity of new bis(thiosemicarbazonato) Cu(II) complexes. J Inorg Biochem 2017; 167:68-79. [DOI: 10.1016/j.jinorgbio.2016.11.026] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 11/18/2016] [Accepted: 11/22/2016] [Indexed: 01/11/2023]
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Colliez F, Gallez B, Jordan BF. Assessing Tumor Oxygenation for Predicting Outcome in Radiation Oncology: A Review of Studies Correlating Tumor Hypoxic Status and Outcome in the Preclinical and Clinical Settings. Front Oncol 2017; 7:10. [PMID: 28180110 PMCID: PMC5263142 DOI: 10.3389/fonc.2017.00010] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 01/10/2017] [Indexed: 12/30/2022] Open
Abstract
Tumor hypoxia is recognized as a limiting factor for the efficacy of radiotherapy, because it enhances tumor radioresistance. It is strongly suggested that assessing tumor oxygenation could help to predict the outcome of cancer patients undergoing radiation therapy. Strategies have also been developed to alleviate tumor hypoxia in order to radiosensitize tumors. In addition, oxygen mapping is critically needed for intensity modulated radiation therapy (IMRT), in which the most hypoxic regions require higher radiation doses and the most oxygenated regions require lower radiation doses. However, the assessment of tumor oxygenation is not yet included in day-to-day clinical practice. This is due to the lack of a method for the quantitative and non-invasive mapping of tumor oxygenation. To fully integrate tumor hypoxia parameters into effective improvements of the individually tailored radiation therapy protocols in cancer patients, methods allowing non-invasively repeated, safe, and robust mapping of changes in tissue oxygenation are required. In this review, non-invasive methods dedicated to assessing tumor oxygenation with the ultimate goal of predicting outcome in radiation oncology are presented, including positron emission tomography used with nitroimidazole tracers, magnetic resonance methods using endogenous contrasts (R1 and R2*-based methods), and electron paramagnetic resonance oximetry; the goal is to highlight results of studies establishing correlations between tumor hypoxic status and patients’ outcome in the preclinical and clinical settings.
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Affiliation(s)
- Florence Colliez
- Biomedical Magnetic Resonance Group, Louvain Drug Research Institute, Université Catholique de Louvain , Brussels , Belgium
| | - Bernard Gallez
- Biomedical Magnetic Resonance Group, Louvain Drug Research Institute, Université Catholique de Louvain , Brussels , Belgium
| | - Bénédicte F Jordan
- Biomedical Magnetic Resonance Group, Louvain Drug Research Institute, Université Catholique de Louvain , Brussels , Belgium
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Lyng H, Malinen E. Hypoxia in cervical cancer: from biology to imaging. Clin Transl Imaging 2017; 5:373-388. [PMID: 28804704 PMCID: PMC5532411 DOI: 10.1007/s40336-017-0238-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 06/24/2017] [Indexed: 12/14/2022]
Abstract
PURPOSE Hypoxia imaging may improve identification of cervical cancer patients at risk of treatment failure and be utilized in treatment planning and monitoring, but its clinical potential is far from fully realized. Here, we briefly describe the biology of hypoxia in cervix tumors of relevance for imaging, and evaluate positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques that have shown promise for assessing hypoxia in a clinical setting. We further discuss emerging imaging approaches, and how imaging can play a role in future treatment strategies to target hypoxia. METHODS We performed a PubMed literature search, using keywords related to imaging and hypoxia in cervical cancer, with a particular emphasis on studies correlating imaging with other hypoxia measures and treatment outcome. RESULTS Only a few and rather small studies have utilized PET with tracers specific for hypoxia, and no firm conclusions regarding preferred tracer or clinical potential can be drawn so far. Most studies address indirect hypoxia imaging with dynamic contrast-enhanced techniques. Strong evidences for a role of these techniques in hypoxia imaging have been presented. Pre-treatment images have shown significant association to outcome in several studies, and images acquired during fractionated radiotherapy may further improve risk stratification. Multiparametric MRI and multimodality PET/MRI enable combined imaging of factors of relevance for tumor hypoxia and warrant further investigation. CONCLUSIONS Several imaging approaches have shown promise for hypoxia imaging in cervical cancer. Evaluation in large clinical trials is required to decide upon the optimal modality and approach.
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Affiliation(s)
- Heidi Lyng
- Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Eirik Malinen
- Department of Medical Physics, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- Department of Physics, University of Oslo, Oslo, Norway
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Nie X, Randolph GJ, Elvington A, Bandara N, Zheleznyak A, Gropler RJ, Woodard PK, Lapi SE. Imaging of hypoxia in mouse atherosclerotic plaques with (64)Cu-ATSM. Nucl Med Biol 2016; 43:534-542. [PMID: 27372286 DOI: 10.1016/j.nucmedbio.2016.05.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Revised: 05/15/2016] [Accepted: 05/25/2016] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Cardiovascular disease is the leading cause of death in the United States. The identification of vulnerable plaque at risk of rupture has been a major focus of research. Hypoxia has been identified as a potential factor in the formation of vulnerable plaque, and it is clear that decreased oxygen plays a role in the development of plaque angiogenesis leading to plaque destabilization. The purpose of this study is to demonstrate the feasibility of copper-64 labeled diacetyl-bis (N(4)-methylthiosemicarbazone) ((64)Cu-ATSM), a positron-emitting radiopharmaceutical taken up in low-oxygen-tension cells, for the identification of hypoxic and potentially unstable atherosclerotic plaque in a mouse model. METHODS (64)Cu-ATSM PET was performed in 21 atherosclerotic apolipoprotein E knockout (ApoE(-/-)) mice, 6 of which were fed high-fat diet (HFD) while the others received standard-chow diet (SCD), and 13 control wild type mice fed SCD. 4 SCD ApoE(-/-) mice and 4 SCD wild type mice also underwent (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) imaging one day prior to (64)Cu-ATSM PET. RESULTS (64)Cu-ATSM uptake was increased in the aortic arch in SCD ApoE(-/-) mice (average aortic arch/muscle (A/M) standardized uptake value ratio 7.5-30min post injection: (5.66±0.23) compared to control mice (A/M SUV ratio 7.5-30min post injection (3.87±0.22), p<0.0001). HFD ApoE(-/-) mice also showed similarly increased aortic arch uptake on PET imaging in comparison to control mice. Immunohistochemistry in both HFD and SCD ApoE(-/-) mice revealed noticeable hypoxia by pimonidazole stain in atherosclerosis which was co-localized to macrophage by CD68 staining. Autoradiography assessment demonstrated the presence of hypoxia by (64)Cu-ATSM uptake correlated with pimonidazole uptake within the ex vivo atherosclerotic aortic arch specimens. A significant increase in (18)F-FDG uptake in the SCD ApoE(-/-) mice in comparison to controls was also observed at delayed time points. CONCLUSION This pre-clinical study suggests that (64)Cu-ATSM is a potential PET tracer for hypoxia imaging in atherosclerosis. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE While studies in humans are necessary for conclusive data, in the long term, a (64)Cu-ATSM PET imaging strategy could help facilitate the study of plaque biology in human patients.
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Affiliation(s)
- Xingyu Nie
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO; Department of Biomedical Engineering, Washington University in St. Louis
| | | | - Andrew Elvington
- Division of Biology and Biomedical Sciences, Washington University in St. Louis
| | - Nilantha Bandara
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO
| | - Alexander Zheleznyak
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO
| | - Robert J Gropler
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO
| | - Pamela K Woodard
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO; Department of Biomedical Engineering, Washington University in St. Louis; Diabetic Cardiovascular Disease Center, Washington University in St. Louis
| | - Suzanne E Lapi
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO; Division of Biology and Biomedical Sciences, Washington University in St. Louis; Department of Biomedical Engineering, Washington University in St. Louis.
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Tsujikawa T, Asahi S, Oh M, Sato Y, Narita N, Makino A, Mori T, Kiyono Y, Tsuchida T, Kimura H, Fujieda S, Okazawa H. Assessment of the Tumor Redox Status in Head and Neck Cancer by 62Cu-ATSM PET. PLoS One 2016; 11:e0155635. [PMID: 27187778 PMCID: PMC4871355 DOI: 10.1371/journal.pone.0155635] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 05/02/2016] [Indexed: 12/23/2022] Open
Abstract
Purpose Tumor redox is an important factor for cancer progression, resistance to treatments, and a poor prognosis. The aim of the present study was to define tumor redox (over-reduction) using 62Cu-diacetyl-bis(N4-methylthiosemicarbazone) (62Cu-ATSM) PET and compare its prognostic potential in head and neck cancer (HNC) with that of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG). Methods Thirty HNC patients (stage II–IV) underwent pretreatment 62Cu-ATSM and 18F-FDG PET scans. Maximum standardized uptake values (SUVATSM and SUVFDG) and tumor-to-muscle activity concentration ratios (TMRATSM and TMRFDG) were measured. Reductive-tumor-volume (RTV) was then determined at four thresholds (40%, 50%, 60%, and 70% SUVATSM), and total-lesion-reduction (TLR) was calculated as the product of the mean SUV and RTV for 62Cu-ATSM. In 18F-FDG, metabolic-tumor-volume (MTV) and total-lesion-glycolysis (TLG) were obtained at a threshold of 40%. A ROC analysis was performed to determine % thresholds for RTV and TLR showing the best predictive performance, and these were then used to determine the optimal cut-off values to stratify patients for each parameter. Progression-free-survival (PFS) and cause-specific-survival (CSS) were evaluated by the Kaplan-Meier method. Results The means ± standard deviations of PFS and CSS periods were 16.4±13.4 and 19.2±12.4 months, respectively. A ROC analysis determined that the 70% SUVATSM threshold for RTV and TLR was the best for predicting disease progression and cancer death. Optimal cut-offs for each index were SUVATSM = 3.6, SUVFDG = 7.9, TMRATSM = 3.2, TMRFDG = 5.6, RTV = 2.9, MTV = 8.1, TLR = 14.0, and TLG = 36.5. When the cut-offs for TMRATSM and TLR were set as described above in 62Cu-ATSM PET, patients with higher TMRATSM (p = 0.03) and greater TLR (p = 0.02) showed significantly worse PFS, while patients with greater TLR had significantly worse CSS (p = 0.02). Only MTV in 18F-FDG PET predicted differences in PSF and CSS (p = 0.03 and p = 0.03, respectively). Conclusion Tumor redox parameters measured by 62Cu-ATSM PET may be determinants of HNC patient outcomes and help define optimal patient-specific treatments.
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Affiliation(s)
- Tetsuya Tsujikawa
- Biomedical Imaging Research Center, University of Fukui, Fukui, Japan
- * E-mail:
| | - Satoko Asahi
- Department of Radiology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Myungmi Oh
- Department of Otolaryngology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yoshitaka Sato
- Department of Radiology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Norihiko Narita
- Department of Otolaryngology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Akira Makino
- Biomedical Imaging Research Center, University of Fukui, Fukui, Japan
| | - Tetsuya Mori
- Biomedical Imaging Research Center, University of Fukui, Fukui, Japan
| | - Yasushi Kiyono
- Biomedical Imaging Research Center, University of Fukui, Fukui, Japan
| | - Tatsuro Tsuchida
- Department of Radiology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Hirohiko Kimura
- Department of Radiology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Shigeharu Fujieda
- Department of Otolaryngology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Hidehiko Okazawa
- Biomedical Imaging Research Center, University of Fukui, Fukui, Japan
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Holland JP, Ferdani R, Anderson CJ, Lewis JS. Copper-64 Radiopharmaceuticals for Oncologic Imaging. PET Clin 2016; 4:49-67. [PMID: 27156895 DOI: 10.1016/j.cpet.2009.04.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The positron emitting radionuclide (64)Cu has a radioactive half-life of 12.7 hours. The decay characteristics of (64)Cu allow for PET images that are comparable in quality to those obtained using (18)F. Given the longer radioactive half-life of (64)Cu compared with (18)F and the versatility of copper chemistry, copper is an attractive alternative to the shorter-lived nuclides for PET imaging of peptides, antibodies, and small molecules that may require longer circulation times. This article discusses a number of copper radiopharmaceuticals, such as Cu-ATSM, that have been translated to the clinic and new developments in copper-based radiopharmaceuticals.
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Affiliation(s)
- Jason P Holland
- Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Riccardo Ferdani
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, Campus Box 8225, St. Louis, MO 63110, USA
| | - Carolyn J Anderson
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, Campus Box 8225, St. Louis, MO 63110, USA
| | - Jason S Lewis
- Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
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Abstract
Tumor hypoxia is a clinically relevant cause of radiation resistance. Direct measurements of tumor oxygenation have been performed predominantly with the Eppendorf histograph and these have defined the reduced prognosis after radiotherapy in poorly oxygenated tumors, especially head-and-neck cancer, cervix cancer and sarcoma. Exogenous markers have been used for immunohistochemical detection of hypoxic tumor areas (pimonidazole) or for positron-emission tomography (PET) imaging (misonidazole). Overexpression of hypoxia-related proteins such as hypoxia-inducible factor-1α (HIF-1α) has also been linked to poor prognosis after radiotherapy and such proteins are considered as potential endogenous hypoxia markers.
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Affiliation(s)
- Dirk Vordermark
- Universitätsklinik und Poliklinik für Strahlentherapie, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany.
| | - Michael R Horsman
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark
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Zschaeck S, Steinbach J, Troost EGC. FMISO as a Biomarker for Clinical Radiation Oncology. Recent Results Cancer Res 2016; 198:189-201. [PMID: 27318688 DOI: 10.1007/978-3-662-49651-0_10] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Tumour hypoxia is a well-known negative prognostic marker in almost all solid tumours. [18F]Fluoromisonidazole (FMISO)-positron emission tomography (PET) is a non-invasive method to detect tumour hypoxia. Compared to other methods of hypoxia assessment it possesses some considerable advantages: It is non-invasive, it delivers spatial information on the hypoxia distribution within the entire tumour volume, and it can be repeated during the course of radio(chemo)therapy. This chapter briefly describes different methods of hypoxia evaluation and focuses on hypoxia PET imaging, with the most commonly used tracer being FMISO. The preclinical rationale and clinical studies to use FMISO-PET for patient stratification in radiation therapy are discussed as well as possible agents or radiation-dose modifications to overcome hypoxia.
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Affiliation(s)
- Sebastian Zschaeck
- OncoRay - National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany. .,German Cancer Consortium (DKTK), Dresden, Germany. .,German Cancer Research Center (DKFZ), Heidelberg, Germany. .,Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.
| | - Jörg Steinbach
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Esther G C Troost
- OncoRay - National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.,German Cancer Consortium (DKTK), Dresden, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.,Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
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Li F, Jørgensen JT, Forman J, Hansen AE, Kjaer A. 64Cu-ATSM Reflects pO2 Levels in Human Head and Neck Cancer Xenografts but Not in Colorectal Cancer Xenografts: Comparison with 64CuCl2. J Nucl Med 2015; 57:437-43. [DOI: 10.2967/jnumed.115.155663] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Accepted: 10/22/2015] [Indexed: 11/16/2022] Open
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Tamaki N, Hirata K. Tumor hypoxia: a new PET imaging biomarker in clinical oncology. Int J Clin Oncol 2015; 21:619-625. [DOI: 10.1007/s10147-015-0920-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 10/20/2015] [Indexed: 01/02/2023]
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Cui YL, Wang X, Li XF. (18)F-fluoromisonidazole PET reveals spatial and temporal heterogeneity of hypoxia in mouse models of human non-small-cell lung cancer. Future Oncol 2015; 11:2841-9. [PMID: 26361064 DOI: 10.2217/fon.15.205] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
AIM To noninvasively observe dynamic changes in tumor hypoxia in mouse models of human non-small-cell lung cancer (NSCLC) using (18)F-fluoromisonidazole PET. MATERIALS & METHODS Nude mice with NSCLC H460 and A549 subcutaneous xenografts were coinjected intravenously with (18)F-fluoromisonidazole and the hypoxia marker pimonidazole, and observed by serial PET scans. After sacrifice, the tumor distribution of (18)F-fluoromisonidazole and pimonidazole was compared by digital autoradiography and microscopy, respectively. RESULTS The NSCLC hypoxic microenvironment was spatially heterogeneous. Serial PET scans over 48 h revealed an apparent change in the intratumoral distribution of (18)F-fluoromisonidazole. CONCLUSION The tumor hypoxic microenvironment is spatially and temporally heterogeneous, and hypoxic cancer cells have a shorter life span when growing in vivo. Therefore, the concept of hypoxic resistance and hypoxia-targeting therapy of macroscopic tumors should be revisited.
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Affiliation(s)
- Ya-Li Cui
- Department of Nuclear Medicine, Harbin Medical University Cancer Hospital, Harbin Heilongjiang, China
| | - Xuemei Wang
- Department of Nuclear Medicine, Inner Mongolia Medical University Affiliated Hospital, Hohhot, Inner Mongolia, China
| | - Xiao-Feng Li
- Department of Radiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
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Furukawa T, Yuan Q, Jin ZH, Aung W, Yoshii Y, Hasegawa S, Endo H, Inoue M, Zhang MR, Fujibayashi Y, Saga T. A limited overlap between intratumoral distribution of 1-(5-fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole and copper-diacetyl-bis[N(4)-methylthiosemicarbazone]. Oncol Rep 2015; 34:1379-1387. [PMID: 26134305 DOI: 10.3892/or.2015.4079] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 06/03/2015] [Indexed: 11/10/2022] Open
Abstract
Positron emission tomography (PET) imaging of tumor hypoxia provides valuable information for cancer treatment planning. Two types of PET tracers, nitroimidazole compounds and [62,64Cu] copper-diacetyl-bis[N(4)-methylthio- semicarbazone] (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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Affiliation(s)
- Takako Furukawa
- Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Qinghua Yuan
- Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Zhao-Hui Jin
- Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Winn Aung
- Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Yukie Yoshii
- Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Sumitaka Hasegawa
- Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Hiroko Endo
- Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | - Masahiro Inoue
- Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | - Ming-Rong Zhang
- Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Yasuhisa Fujibayashi
- Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Tsuneo Saga
- Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
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Colombié M, Gouard S, Frindel M, Vidal A, Chérel M, Kraeber-Bodéré F, Rousseau C, Bourgeois M. Focus on the Controversial Aspects of (64)Cu-ATSM in Tumoral Hypoxia Mapping by PET Imaging. Front Med (Lausanne) 2015; 2:58. [PMID: 26380261 PMCID: PMC4547458 DOI: 10.3389/fmed.2015.00058] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 08/10/2015] [Indexed: 11/13/2022] Open
Abstract
Mapping tumor hypoxia is a great challenge in positron emission tomography (PET) imaging as the precise functional information of the biological processes is needed for many effective therapeutic strategies. Tumor hypoxia has been widely reported as a poor prognostic indicator and is often associated with tumor aggressiveness, chemo- and radio-resistance. An accurate diagnosis of hypoxia is a challenge and is crucial for providing accurate treatment for patients' survival benefits. This challenge has led to the emergence of new and novel PET tracers for the functional and metabolic characterization of tumor hypoxia non-invasively. Among these tracers, copper semicarbazone compound [64Cu]-diacetyl-bis(N (4)-methylthiosemicarbazone) (=64Cu-ATSM) has been developed as a tracer for hypoxia imaging. This review focuses on 64Cu-ATSM PET imaging and the concept is presented in two sections. The first section describes its in vitro development and pre-clinical testing and particularly its affinity in different cell lines. The second section describes the controversial reports on its specificity for hypoxia imaging. The review concludes that 64Cu-ATSM - more than a hypoxic tracer, exhibits tracer accumulation in tumor, which is linked to the redox potential and reactive oxygen species. The authors concluded that 64Cu-ATSNM is a marker of over-reduced cell state and thus an indirect marker for hypoxia imaging. The affinity of 64Cu-ATSM for over-reduced cells was observed to be a complex phenomenon. And to provide a definitive and convincing mechanism, more in vivo studies are needed to prove the diagnostic utility of 64Cu-ATSM.
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Affiliation(s)
| | | | | | | | - Michel Chérel
- Institut de Cancérologie de l'Ouest , Saint-Herblain , France ; CRCNA, INSERM, Université de Nantes , Nantes , France
| | - Françoise Kraeber-Bodéré
- Institut de Cancérologie de l'Ouest , Saint-Herblain , France ; CRCNA, INSERM, Université de Nantes , Nantes , France ; Service de Médecine Nucléaire - CHU de Nantes , Nantes , France
| | - Caroline Rousseau
- Institut de Cancérologie de l'Ouest , Saint-Herblain , France ; CRCNA, INSERM, Université de Nantes , Nantes , France
| | - Mickaël Bourgeois
- CRCNA, INSERM, Université de Nantes , Nantes , France ; GIP ARRONAX , Saint-Herblain , France ; Service de Médecine Nucléaire - CHU de Nantes , Nantes , France
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Yip C, Blower PJ, Goh V, Landau DB, Cook GJR. Molecular imaging of hypoxia in non-small-cell lung cancer. Eur J Nucl Med Mol Imaging 2015; 42:956-76. [PMID: 25701238 DOI: 10.1007/s00259-015-3009-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 01/26/2015] [Indexed: 12/18/2022]
Abstract
Non-small-cell lung cancer (NSCLC) is the commonest cancer worldwide but survival remains poor with a high risk of relapse, particularly after nonsurgical treatment. Hypoxia is present in a variety of solid tumours, including NSCLC. It is associated with treatment resistance and a poor prognosis, although when recognised may be amenable to different treatment strategies. Thus, noninvasive assessment of intratumoral hypoxia could be used to stratify patients for modification of subsequent treatment to improve tumour control. Molecular imaging approaches targeting hypoxic cells have shown some early success in the clinical setting. This review evaluates the evidence for hypoxia imaging using PET in NSCLC and explores its potential clinical utility.
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Affiliation(s)
- Connie Yip
- Department of Cancer Imaging, Division of Imaging Sciences & Biomedical Engineering, King's College London, St Thomas' Hospital, London, UK,
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Hueting R, Kersemans V, Tredwell M, Cornelissen B, Christlieb M, Gee AD, Passchier J, Smart SC, Gouverneur V, Muschel RJ, Dilworth JR. A dual radiolabelling approach for tracking metal complexes: investigating the speciation of copper bis(thiosemicarbazonates) in vitro and in vivo. Metallomics 2015; 7:795-804. [PMID: 25768310 DOI: 10.1039/c4mt00330f] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Copper(II)bis(thiosemicarbazonato) complexes such as [(64)Cu]Cu-ATSM continue to be investigated for positron emission tomography (PET) imaging of tumour hypoxia. However, the currently proposed mechanisms for the mode of action of these complexes are unable to account fully for their observed biological behaviour. In order to examine the roles of the copper metal and the ligand, we designed a pair of (123)I/(64)Cu-copper bis(thiosemicarbazonates), radiolabelled at either the metal or at the ligand. In vitro cellular retention studies of the orthogonal pair demonstrate for the first time that retention under hypoxia involves dissociation of the copper bis(thiosemicarbazone) complex, consistent with the previously suggested mechanism of reductive trapping of copper. In contrast, in vivo biodistribution and dynamic PET/SPECT imaging of the orthogonally labelled complexes underline our previous findings for [(64)Cu]Cu-ATSM and [(64)Cu]Cu-acetate, providing further support for the important contribution of copper metabolism in the in vivo hypoxia selectivity of Cu-ATSM. This dual radiolabelling approach may find applications for determining the speciation of other metal complexes in vitro and in vivo.
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Affiliation(s)
- Rebekka Hueting
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Rd, Oxford, OX1 3TA, UK.
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van Dijk LK, Boerman OC, Kaanders JH, Bussink J. PET Imaging in Head and Neck Cancer Patients to Monitor Treatment Response: A Future Role for EGFR-Targeted Imaging. Clin Cancer Res 2015; 21:3602-9. [DOI: 10.1158/1078-0432.ccr-15-0348] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 03/20/2015] [Indexed: 11/16/2022]
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Pharmacokinetic Analysis of (64)Cu-ATSM Dynamic PET in Human Xenograft Tumors in Mice. Diagnostics (Basel) 2015; 5:96-112. [PMID: 26854145 PMCID: PMC4665587 DOI: 10.3390/diagnostics5020096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 03/05/2015] [Accepted: 03/09/2015] [Indexed: 11/17/2022] Open
Abstract
UNLABELLED The aim of this study was to evaluate the feasibility to perform voxel-wise kinetic modeling on datasets obtained from tumor-bearing mice that underwent dynamic PET scans with (64)Cu-ATSM and extract useful physiological parameters. METHODS Tumor-bearing mice underwent 90-min dynamic PET scans with (64)Cu-ATSM and CT scans with contrast. Irreversible and reversible two-tissue compartment models were fitted to time activity curves (TACs) obtained from whole tumor volumes and compared using the Akaike information criterion (AIC). Based on voxel-wise pharmacokinetic analysis, parametric maps of model rate constants k₁, k₃ and Ki were generated and compared to (64)Cu-ATSM uptake. RESULTS Based on the AIC, an irreversible two-tissue compartment model was selected for voxel-wise pharmacokinetic analysis. Of the extracted parameters, k₁ (~perfusion) showed a strong correlation with early tracer uptake (mean spearman R = 0.88) 5 min post injection (pi). Moreover, positive relationships were found between late tracer uptake (90 min pi) and both k₃ and the net influx rate constant, Ki (mean spearman R = 0.56 and R = 0.86; respectively). CONCLUSION This study shows the feasibility to extract relevant parameters from voxel-wise pharmacokinetic analysis to be used for preclinical validation of (64)Cu-ATSM as a hypoxia-specific PET tracer.
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Fleming IN, Manavaki R, Blower PJ, West C, Williams KJ, Harris AL, Domarkas J, Lord S, Baldry C, Gilbert FJ. Imaging tumour hypoxia with positron emission tomography. Br J Cancer 2015; 112:238-50. [PMID: 25514380 PMCID: PMC4453462 DOI: 10.1038/bjc.2014.610] [Citation(s) in RCA: 246] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 09/30/2014] [Accepted: 11/10/2014] [Indexed: 01/02/2023] Open
Abstract
Hypoxia, a hallmark of most solid tumours, is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. Given its prominent role in oncology, accurate detection of hypoxia is important, as it impacts on prognosis and could influence treatment planning. A variety of approaches have been explored over the years for detecting and monitoring changes in hypoxia in tumours, including biological markers and noninvasive imaging techniques. Positron emission tomography (PET) is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. This review provides an overview of imaging hypoxia with PET, with an emphasis on the advantages and limitations of the currently available hypoxia radiotracers.
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Affiliation(s)
- I N Fleming
- Aberdeen Biomedical Imaging Centre, Lilian Sutton Building, Foresterhill, Aberdeen AB25 2ZD, UK
| | - R Manavaki
- Department of Radiology, School of Clinical Medicine, University of Cambridge, Box 218-Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
| | - P J Blower
- Division of Imaging Sciences and Biomedical Engineering, St Thomas' Hospital, King's College London, 4th Floor, Lambeth Wing, London SE1 7EH, UK
| | - C West
- Manchester Academic Health Science Centre, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
| | - K J Williams
- Manchester Pharmacy School, Faculty of Medical and Human Sciences, University Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
- EPSRC and CRUK Cancer Imaging Centre in Cambridge and Manchester, Cambridge, UK
| | - A L Harris
- Molecular Oncology Laboratories, University Department of Medical Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK
| | - J Domarkas
- Centre for Cardiovascular and Metabolic Research, Respiratory Medicine, Hull-York Medical School, University of Hull, Hull HU16 5JQ, UK
| | - S Lord
- Molecular Oncology Laboratories, University Department of Medical Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK
| | - C Baldry
- Division of Imaging Sciences and Biomedical Engineering, St Thomas' Hospital, King's College London, 4th Floor, Lambeth Wing, London SE1 7EH, UK
| | - F J Gilbert
- Department of Radiology, School of Clinical Medicine, University of Cambridge, Box 218-Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
- EPSRC and CRUK Cancer Imaging Centre in Cambridge and Manchester, Cambridge, UK
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Verwer EE, Boellaard R, Veldt AAMVD. Positron emission tomography to assess hypoxia and perfusion in lung cancer. World J Clin Oncol 2014; 5:824-844. [PMID: 25493221 PMCID: PMC4259945 DOI: 10.5306/wjco.v5.i5.824] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Revised: 04/29/2014] [Accepted: 07/15/2014] [Indexed: 02/06/2023] Open
Abstract
In lung cancer, tumor hypoxia is a characteristic feature, which is associated with a poor prognosis and resistance to both radiation therapy and chemotherapy. As the development of tumor hypoxia is associated with decreased perfusion, perfusion measurements provide more insight into the relation between hypoxia and perfusion in malignant tumors. Positron emission tomography (PET) is a highly sensitive nuclear imaging technique that is suited for non-invasive in vivo monitoring of dynamic processes including hypoxia and its associated parameter perfusion. The PET technique enables quantitative assessment of hypoxia and perfusion in tumors. To this end, consecutive PET scans can be performed in one scan session. Using different hypoxia tracers, PET imaging may provide insight into the prognostic significance of hypoxia and perfusion in lung cancer. In addition, PET studies may play an important role in various stages of personalized medicine, as these may help to select patients for specific treatments including radiation therapy, hypoxia modifying therapies, and antiangiogenic strategies. In addition, specific PET tracers can be applied for monitoring therapy. The present review provides an overview of the clinical applications of PET to measure hypoxia and perfusion in lung cancer. Available PET tracers and their characteristics as well as the applications of combined hypoxia and perfusion PET imaging are discussed.
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PET, MRI, and simultaneous PET/MRI in the development of diagnostic and therapeutic strategies for glioma. Drug Discov Today 2014; 20:306-17. [PMID: 25448762 DOI: 10.1016/j.drudis.2014.10.016] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Revised: 10/15/2014] [Accepted: 10/30/2014] [Indexed: 11/21/2022]
Abstract
Glioma is the most aggressive brain tumour, resulting in death often within 1-2 years. Current treatment strategies involve surgical resection followed by chemoradiation therapy. Despite continuing improvements in the delivery of adjuvant therapies, there has not been a dramatic increase in survival for glioma. Molecular imaging techniques have become central in the development of new therapeutic strategies in recent years. The multimodal imaging technology of positron emission tomography/magnetic resonance imaging (PET/MRI) has recently been realised on a preclinical scale and the effect of this technology is starting to be observed in preclinical drug development for glioma. Here, we propose that PET/MRI will play an integral part in the development of new diagnostic and therapeutic strategies for glioma.
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Clausen MM, Hansen AE, Lundemann M, Hollensen C, Pommer T, Munck Af Rosenschöld P, Kristensen AT, Kjær A, McEvoy FJ, Engelholm SA. Dose painting based on tumor uptake of Cu-ATSM and FDG: a comparative study. Radiat Oncol 2014; 9:228. [PMID: 25319766 PMCID: PMC4203925 DOI: 10.1186/s13014-014-0228-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 10/02/2014] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Hypoxia and increased glycolytic activity of tumors are associated with poor prognosis. The purpose of this study was to investigate differences in radiotherapy (RT) dose painting based on the uptake of 2-deoxy-2-[(18) F]-fluorodeoxyglucose (FDG) and the proposed hypoxia tracer, copper(II)diacetyl-bis(N(4))-methylsemithiocarbazone (Cu-ATSM) using spontaneous clinical canine tumor models. METHODS Positron emission tomography/computed tomography scans of five spontaneous canine sarcomas and carcinomas were obtained; FDG on day 1 and (64)Cu-ATSM on day 2 and 3 (approx. 3 and 24 hours pi.). Sub-volumes for dose escalation were defined by a threshold-based method for both tracers and five dose escalation levels were formed in each sub-volume. Volumetric modulated arc therapy plans were optimized based on the dose escalation regions for each scan for a total of three dose plans for each dog. The prescription dose for the GTV was 45 Gy (100%) and it was linearly escalated to a maximum of 150%. The correlations between dose painting plans were analyzed with construction of dose distribution density maps and quality volume histograms (QVH). Correlation between high-dose regions was investigated with Dice correlation coefficients. RESULTS Comparison of dose plans revealed varying degree of correlation between cases. Some cases displayed a separation of high-dose regions in the comparison of FDG vs. (64)Cu-ATSM dose plans at both time points. Among the Dice correlation coefficients, the high dose regions showed the lowest degree of agreement, indicating potential benefit of using multiple tracers for dose painting. QVH analysis revealed that FDG-based dose painting plans adequately covered approximately 50% of the hypoxic regions. CONCLUSION Radiotherapy plans optimized with the current approach for cut-off values and dose region definitions based on FDG, (64)Cu-ATSM 3 h and 24 h uptake in canine tumors had different localization of the regional dose escalation levels. This indicates that (64)Cu-ATSM at two different time-points and FDG provide different biological information that has to be taken into account when using the dose painting strategy in radiotherapy treatment planning.
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Affiliation(s)
- Malene Martini Clausen
- Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. .,Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. .,Department of Veterinary Clinical and Animal Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Anders Elias Hansen
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. .,Technical University of Denmark, DTU Nanotech, Center of Nanomedicine and theranostics, Lyngby, Denmark.
| | - Michael Lundemann
- Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
| | - Christian Hollensen
- Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
| | - Tobias Pommer
- Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. .,Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.
| | - Per Munck Af Rosenschöld
- Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. .,Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.
| | | | - Andreas Kjær
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
| | - Fintan J McEvoy
- Department of Veterinary Clinical and Animal Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Svend Aage Engelholm
- Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
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Cochet A, Kanoun S, Humbert O, Walker PM, Cormier L, Créhange G, Brunotte F. Quelle imagerie pour la prise en charge de la rechute biochimique du cancer de la prostate : TEP ou IRM ? Cancer Radiother 2014; 18:509-16. [DOI: 10.1016/j.canrad.2014.07.148] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 07/15/2014] [Accepted: 07/16/2014] [Indexed: 12/25/2022]
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Detailed assessment of gene activation levels by multiple hypoxia-responsive elements under various hypoxic conditions. Ann Nucl Med 2014; 28:1011-9. [PMID: 25249501 PMCID: PMC4483249 DOI: 10.1007/s12149-014-0901-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 08/24/2014] [Indexed: 11/03/2022]
Abstract
OBJECTIVE HIF-1/HRE pathway is a promising target for the imaging and the treatment of intractable malignancy (HIF-1; hypoxia-inducible factor 1, HRE; hypoxia-responsive element). The purposes of our study are: (1) to assess the gene activation levels resulting from various numbers of HREs under various hypoxic conditions, (2) to evaluate the bidirectional activity of multiple HREs, and (3) to confirm whether multiple HREs can induce gene expression in vivo. METHODS Human colon carcinoma HCT116 cells were transiently transfected by the constructs containing a firefly luciferase reporter gene and various numbers (2, 4, 6, 8, 10, and 12) of HREs (nHRE+, nHRE-). The relative luciferase activities were measured under various durations of hypoxia (6, 12, 18, and 24 h), O2 concentrations (1, 2, 4, 8, and 16 %), and various concentrations of deferoxamine mesylate (20, 40, 80, 160, and 320 µg/mL growth medium). The bidirectional gene activation levels by HREs were examined in the constructs (dual-luc-nHREs) containing firefly and Renilla luciferase reporter genes at each side of nHREs. Finally, to test whether the construct containing 12HRE and the NIS reporter gene (12HRE-NIS) can induce gene expression in vivo, SPECT imaging was performed in a mouse xenograft model. RESULTS (1) gene activation levels by HREs tended to increase with increasing HRE copy number, but a saturation effect was observed in constructs with more than 6 or 8 copies of an HRE, (2) gene activation levels by HREs increased remarkably during 6-12 h of hypoxia, but not beyond 12 h, (3) gene activation levels by HREs decreased with increasing O2 concentrations, but could be detected even under mild hypoxia at 16 % O2, (4) the bidirectionally proportional activity of the HRE was confirmed regardless of the hypoxic severity, and (5) NIS expression driven by 12 tandem copies of an HRE in response to hypoxia could be visualized on in vivo SPECT imaging. CONCLUSION The results of this study will help in the understanding and assessment of the activity of multiple HREs under hypoxia and become the basis for hypoxia-targeted imaging and therapy in the future.
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Peitzsch C, Perrin R, Hill RP, Dubrovska A, Kurth I. Hypoxia as a biomarker for radioresistant cancer stem cells. Int J Radiat Biol 2014; 90:636-52. [DOI: 10.3109/09553002.2014.916841] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Bradshaw TJ, Yip S, Jallow N, Forrest LJ, Jeraj R. Spatiotemporal stability of Cu-ATSM and FLT positron emission tomography distributions during radiation therapy. Int J Radiat Oncol Biol Phys 2014; 89:399-405. [PMID: 24685446 DOI: 10.1016/j.ijrobp.2014.02.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 01/06/2014] [Accepted: 02/12/2014] [Indexed: 12/09/2022]
Abstract
PURPOSE In dose painting, in which functional imaging is used to define biological targets for radiation therapy dose escalation, changes in spatial distributions of biological properties during treatment can compromise the quality of therapy. The goal of this study was to assess the spatiotemporal stability of 2 potential dose painting targets--hypoxia and proliferation--in canine tumors during radiation therapy. METHODS AND MATERIALS Twenty-two canine patients with sinonasal tumors (14 carcinoma and 8 sarcoma) were imaged before hypofractionated radiation therapy with copper(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) positron emission tomography/computed tomography (PET/CT) for hypoxia and 3'-deoxy-3'-(18)F-fluorothymidine (FLT) PET/CT for proliferation. The FLT scans were repeated after 2 fractions and the Cu-ATSM scans after 3 fractions. Midtreatment PET/CT images were deformably registered to pretreatment PET/CT images. Voxel-based Spearman correlation coefficients quantified the spatial stability of Cu-ATSM and FLT uptake distributions between pretreatment and midtreatment scans. Paired t tests determined significant differences between the patients' respective Cu-ATSM and FLT correlations coefficients. Standardized uptake value measures were also compared between pretreatment and midtreatment scans by use of paired t tests. RESULTS Spatial distributions of Cu-ATSM and FLT uptake were stable through midtreatment for both sarcomas and carcinomas: the population mean ± standard deviation in Spearman correlation coefficient was 0.88 ± 0.07 for Cu-ATSM and 0.79 ± 0.13 for FLT. The patients' Cu-ATSM correlation coefficients were significantly higher than their respective FLT correlation coefficients (P=.001). Changes in Cu-ATSM SUV measures from pretreatment to midtreatment were histology dependent: carcinomas experienced significant decreases in Cu-ATSM uptake (P<.05), whereas sarcomas did not (P>.20). Both histologies experienced significant decreases in FLT uptake (P<.05). CONCLUSIONS Spatial distributions of Cu-ATSM were very stable after a few fractions of radiation therapy. FLT spatial distributions were generally stable early in therapy, although they were significantly less stable than Cu-ATSM distributions. Canine tumors had significantly lower proliferative activity at midtreatment than at pretreatment, and they experienced histology-dependent changes in Cu-ATSM uptake.
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Affiliation(s)
- Tyler J Bradshaw
- Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Stephen Yip
- Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Ngoneh Jallow
- Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Lisa J Forrest
- Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin
| | - Robert Jeraj
- Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
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Kelada OJ, Carlson DJ. Molecular imaging of tumor hypoxia with positron emission tomography. Radiat Res 2014; 181:335-49. [PMID: 24673257 DOI: 10.1667/rr13590.1] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The problem of tumor hypoxia has been recognized and studied by the oncology community for over 60 years. From radiation and chemotherapy resistance to the increased risk of metastasis, low oxygen concentrations in tumors have caused patients with many types of tumors to respond poorly to conventional cancer therapies. It is clear that patients with high levels of tumor hypoxia have a poorer overall treatment response and that the magnitude of hypoxia is an important prognostic factor. As a result, the development of methods to measure tumor hypoxia using invasive and noninvasive techniques has become desirable to the clinical oncology community. A variety of imaging modalities have been established to visualize hypoxia in vivo. Positron emission tomography (PET) imaging, in particular, has played a key role for imaging tumor hypoxia because of the development of hypoxia-specific radiolabelled agents. Consequently, this technique is increasingly used in the clinic for a wide variety of cancer types. Following a broad overview of the complexity of tumor hypoxia and measurement techniques to date, this article will focus specifically on the accuracy and reproducibility of PET imaging to quantify tumor hypoxia. Despite numerous advances in the field of PET imaging for hypoxia, we continue to search for the ideal hypoxia tracer to both qualitatively and quantitatively define the tumor hypoxic volume in a clinical setting to optimize treatments and predict response in cancer patients.
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Affiliation(s)
- Olivia J Kelada
- a Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut; and
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Hueting R. Radiocopper for the imaging of copper metabolism. J Labelled Comp Radiopharm 2014; 57:231-8. [DOI: 10.1002/jlcr.3155] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Accepted: 10/29/2013] [Indexed: 12/12/2022]
Affiliation(s)
- Rebekka Hueting
- Division of Imaging Sciences & Biomedical Engineering; King's College London, St. Thomas' Hospital; London UK
- Chemistry Research Laboratory; University of Oxford; Oxford UK
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Zeglis BM, Houghton JL, Evans MJ, Viola-Villegas N, Lewis JS. Underscoring the influence of inorganic chemistry on nuclear imaging with radiometals. Inorg Chem 2014; 53:1880-99. [PMID: 24313747 PMCID: PMC4151561 DOI: 10.1021/ic401607z] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Over the past several decades, radionuclides have matured from largely esoteric and experimental technologies to indispensible components of medical diagnostics. Driving this transition, in part, have been mutually necessary advances in biomedical engineering, nuclear medicine, and cancer biology. Somewhat unsung has been the seminal role of inorganic chemistry in fostering the development of new radiotracers. In this regard, the purpose of this Forum Article is to more visibly highlight the significant contributions of inorganic chemistry to nuclear imaging by detailing the development of five metal-based imaging agents: (64)Cu-ATSM, (68)Ga-DOTATOC, (89)Zr-transferrin, (99m)Tc-sestamibi, and (99m)Tc-colloids. In a concluding section, several unmet needs both in and out of the laboratory will be discussed to stimulate conversation between inorganic chemists and the imaging community.
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Affiliation(s)
- Brian M. Zeglis
- Department of Radiology and the Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
| | - Jacob L. Houghton
- Department of Radiology and the Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
| | - Michael J. Evans
- Department of Radiology and the Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
| | - Nerissa Viola-Villegas
- Department of Radiology and the Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
| | - Jason S. Lewis
- Department of Radiology and the Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
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Carlin S, Zhang H, Reese M, Ramos NN, Chen Q, Ricketts SA. A comparison of the imaging characteristics and microregional distribution of 4 hypoxia PET tracers. J Nucl Med 2014; 55:515-21. [PMID: 24491409 DOI: 10.2967/jnumed.113.126615] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
UNLABELLED We compared the imaging characteristics and hypoxia selectivity of 4 hypoxia PET radiotracers ((18)F-fluoromisonidazole [(18)F-FMISO], (18)F-flortanidazole [(18)F-HX4], (18)F-fluoroazomycin arabinoside [(18)F-FAZA], and (64)Cu-diacetyl-bis(N4-methylsemicarbazone) [(64)Cu-ATSM]) in a single murine xenograft tumor model condition using small-animal PET imaging and combined ex vivo autoradiography and fluorescence immunohistochemistry. METHODS Nude mice bearing SQ20b xenograft tumors were administered 1 of 4 hypoxia PET tracers and images acquired 80-90 min after injection. Frozen sections from excised tumors were then evaluated for tracer distribution using digital autoradiography and compared with histologic markers of tumor hypoxia (pimonidazole, carbonic anydrase 9 [CA9]) and vascular perfusion (Hoechst 33342). RESULTS The highest tumor uptake was observed with (64)Cu-ATSM (maximum standardized uptake values [SUV(max)], 1.26 ± 0.13) and the lowest with (18)F-FAZA (SUVmax, 0.41 ± 0.24). (18)F-FMISO and (18)F-HX4 had similar intermediate tumor uptake (SUV(max), 0.76 ± 0.38 and 0.65 ± 0.19, respectively). Digital autoradiographs of hypoxia tracer distribution were compared pixel by pixel with images of immunohistochemistry stains. The fluorinated nitroimidazoles all showed radiotracer uptake increasing with pimonidazole and CA9 staining. (64)Cu-ATSM showed the opposite pattern, with highest radiotracer uptake observed in regions with the lowest pimonidazole and CA9 staining. CONCLUSION The fluorinated nitroimidazoles showed similar tumor distributions when compared with immunohistochemistry markers of hypoxia. Variations in tumor standardized uptake value and normal tissue distribution may determine the most appropriate clinical setting for each tracer. (64)Cu-ATSM showed the highest tumor accumulation and little renal clearance. However, the lack of correlation between (64)Cu-ATSM distribution and immunohistochemistry hypoxia markers casts some doubt on the hypoxia selectivity of (64)Cu-ATSM.
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Affiliation(s)
- Sean Carlin
- Radiochemistry and Imaging Sciences Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York
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Hueting R, Kersemans V, Cornelissen B, Tredwell M, Hussien K, Christlieb M, Gee AD, Passchier J, Smart SC, Dilworth JR, Gouverneur V, Muschel RJ. A comparison of the behavior of (64)Cu-acetate and (64)Cu-ATSM in vitro and in vivo. J Nucl Med 2014; 55:128-34. [PMID: 24337603 DOI: 10.2967/jnumed.113.119917] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
UNLABELLED (64)Cu-diacetyl-bis(N(4)-methylthiosemicarbazonate), (64)Cu-ATSM, continues to be investigated clinically as a PET agent both for delineation of tumor hypoxia and as an effective indicator of patient prognosis, but there are still aspects of the mechanism of action that are not fully understood. METHODS The retention of radioactivity in tumors after administration of (64)Cu-ATSM in vivo is substantially higher for tumors with a significant hypoxic fraction. This hypoxia-dependent retention is believed to involve the reduction of Cu-ATSM, followed by the loss of copper to cellular copper processing. To shed light on a possible role of copper metabolism in hypoxia targeting, we have compared (64)Cu retention in vitro and in vivo in CaNT and EMT6 cells or cancers after the administration of (64)Cu-ATSM or (64)Cu-acetate. RESULTS In vivo in mice bearing CaNT or EMT6 tumors, biodistributions and dynamic PET data are broadly similar for (64)Cu-ATSM and (64)Cu-acetate. Copper retention in tumors at 15 min is higher after injection of (64)Cu-acetate than (64)Cu-ATSM, but similar values result at 2 and 16 h for both. Colocalization with hypoxia as measured by EF5 immunohistochemistry is evident for both at 16 h after administration but not at 15 min or 2 h. Interestingly, at 2 h tumor retention for (64)Cu-acetate and (64)Cu-ATSM, although not colocalizing with hypoxia, is reduced by similar amounts by increased tumor oxygenation due to inhalation of increased O2. In vitro, substantially less uptake is observed for (64)Cu-acetate, although this uptake had some hypoxia selectivity. Although (64)Cu-ATSM is stable in mouse serum alone, there is rapid disappearance of intact complex from the blood in vivo and comparable amounts of serum bound activity for both (64)Cu-ATSM and (64)Cu-acetate. CONCLUSION That in vivo, in the EMT6 and CaNT tumors studied, the distribution of radiocopper from (64)Cu-ATSM in tumors essentially mirrors that of (64)Cu-acetate suggests that copper metabolism may also play a role in the mechanism of selectivity of Cu-ATSM.
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Affiliation(s)
- Rebekka Hueting
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom
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