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Yoshino Y, Yoshino F, Aoki I, Mori Y, Suzuki G, Tsuji S, Amano T, Shiino A, Chano T, Furusho Y, Murakami T, Yamazaki H, Yamada K. 2-Nitroimidazole-Functionalized Superparamagnetic Iron Oxide Nanoparticles Detect Hypoxic Regions of Glioblastomas on MRI and Improve Radiotherapy Efficacy. ACS NANO 2025; 19:12762-12776. [PMID: 40139197 PMCID: PMC11984306 DOI: 10.1021/acsnano.4c06753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 03/10/2025] [Accepted: 03/11/2025] [Indexed: 03/29/2025]
Abstract
The presence of hypoxic regions in tumors is associated with malignancy and is an important target for the high-precision diagnosis and treatment of tumors. Radioresistant hypoxic regions can be precisely identified and treated without the use of high doses of radiation if hypoxic region-specific contrast agents have a therapeutic effect. In this study, we synthesized a therapeutic-diagnostic complex agent (SPION-PG-NI) by combining polyglycerol-functionalized superparamagnetic iron oxide nanoparticles (SPION-PG, core diameter of 8.8 ± 1.9 nm) as an MRI contrast agent and 2-nitroimidazole (NI, a pimonidazole derivative) as a hypoxia-targeted ligand to visually evaluate hypoxic regions using MRI and improve radiotherapy efficacy at those sites. SPION-PG-NI showed a concentration-dependent contrast effect and had significantly higher accumulation in subcutaneous glioblastomas than the control agent, SPION-PG, 24 h after administration. Immunohistological evaluations showed that the SPION-PG-NI-accumulated regions corresponded well to hypoxic regions. SPION-PG-NI showed neither migration into the brain parenchyma nor neurotoxicity. Both SPION-PG and SPION-PG-NI decrease reactive oxygen species (ROS); however, they improve radiotherapy efficacy in hypoxic glioblastoma cells due to cytotoxicity. This effect of SPION-PG-NI was significantly higher than that of SPION-PG (p < 0.01). After 12 Gy irradiation, the mean normalized glioblastoma tumor volume on day 38 in the SPION-PG-NI group (288%) was significantly lower than that in the control group (882%) (p < 0.05). Collectively, these findings suggest the potential of SPION-PG-NI as a useful and safe tumor theranostic nanodevice for hypoxic imaging and improving radiotherapy efficacy.
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Affiliation(s)
- Yuki Yoshino
- Department
of Radiology, Kyoto Prefectural University
of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
- Kansai
BNCT Medical Center, Educational Foundation
of Osaka Medical and Pharmaceutical University, 2-7 Daigakucho, Takatsuki Osaka 569-8686, Japan
| | - Fumi Yoshino
- Department
of Obstetrics and Gynecology, Shiga University
of Medical Science, Seta, Otsu 520-2192, Japan
- Mariko
Clinic, 13-5 Noji, Kusatsu 525-0059, Japan
| | - Ichio Aoki
- Institute
for Quantum Medical Science, National Institutes
for Quantum Science and Technology (QST), Anagawa 4-9-1, Inage 263-8555 Chiba, Japan
| | - Yasuyuki Mori
- Department
of Chemistry, Shiga University of Medical
Science, Otsu 520-2192, Japan
| | - Gen Suzuki
- Department
of Radiology, Kyoto Prefectural University
of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Shunichiro Tsuji
- Department
of Obstetrics and Gynecology, Shiga University
of Medical Science, Seta, Otsu 520-2192, Japan
| | - Tsukuru Amano
- Department
of Obstetrics and Gynecology, Shiga University
of Medical Science, Seta, Otsu 520-2192, Japan
| | - Akihiko Shiino
- Department
of Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu 520-2192, Japan
| | - Tokuhiro Chano
- Department
of Clinical Laboratory Medicine, Shiga University
of Medical Science, Seta, Otsu 520-2192, Japan
| | - Yoshio Furusho
- Department
of Chemistry, Shiga University of Medical
Science, Otsu 520-2192, Japan
| | - Takashi Murakami
- Department
of Obstetrics and Gynecology, Shiga University
of Medical Science, Seta, Otsu 520-2192, Japan
| | - Hideya Yamazaki
- Department
of Radiology, Kyoto Prefectural University
of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Kei Yamada
- Department
of Radiology, Kyoto Prefectural University
of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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Xu X, Tang X, Wu W, Liu M, Zeng J. Radiopharmaceuticals in Nasopharyngeal Cancer. Bioorg Chem 2025; 157:108281. [PMID: 40015109 DOI: 10.1016/j.bioorg.2025.108281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 02/11/2025] [Accepted: 02/13/2025] [Indexed: 03/01/2025]
Abstract
Nasopharyngeal carcinoma (NPC) is a prevalent malignant epithelial tumor and epidemic in East and Southeast Asia. The pathology of NPC was characterized by local infiltration early, regional nodal involvement and distant metastases. The specialty of pathological sites makes it hard to early diagnosis, which relies on multiple imaging techniques (MRI, CT scans, and endoscopy) and biopsy. Precise staging of NPC and targeted therapies are vital to the therapeutic efficacy and prognosis. Noninvasive and high-resolution imaging techniques are urgently needed for NPC. Radiopharmaceuticals and imaging equipment (single-photon emission computed tomography (SPECT) and positron emission tomography (PET)) are rapidly developed and applied in the diagnosis of NPC. In this review, we summarized the radiopharmaceuticals in NPC. Reviewing the radiopharmaceuticals in NPC would greatly help further optimize the radioligands and discover novel targets.
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Affiliation(s)
- Xiaoquan Xu
- Department of Otolaryngology, The ChenJiaqiao Hospital of ShaPingba District of Chongqing (The Affiliated Hospital of Chongqing Medical and Pharmaceutical College), ShaPingba District, Chongqing, China.
| | - Xuemei Tang
- Department of Otolaryngology, The ChenJiaqiao Hospital of ShaPingba District of Chongqing (The Affiliated Hospital of Chongqing Medical and Pharmaceutical College), ShaPingba District, Chongqing, China
| | - Wenmin Wu
- Department of Otolaryngology, The ChenJiaqiao Hospital of ShaPingba District of Chongqing (The Affiliated Hospital of Chongqing Medical and Pharmaceutical College), ShaPingba District, Chongqing, China
| | - Min Liu
- Department of Otolaryngology, The ChenJiaqiao Hospital of ShaPingba District of Chongqing (The Affiliated Hospital of Chongqing Medical and Pharmaceutical College), ShaPingba District, Chongqing, China
| | - Junqing Zeng
- Department of Otolaryngology, Pingshan District People's Hospital of Shenzhen, Pingshan Hospital of Southern Medical University, Shenzhen, Guangdong, China.
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Zhang R, Shen Y, Zhou X, Li J, Zhao H, Zhang Z, Zhao J, Jin H, Guo S, Ding H, Nie G, Zhang Z, Wang Y, Yan X, Fan K. Hypoxia-tropic delivery of nanozymes targeting transferrin receptor 1 for nasopharyngeal carcinoma radiotherapy sensitization. Nat Commun 2025; 16:890. [PMID: 39837820 PMCID: PMC11751138 DOI: 10.1038/s41467-025-56134-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 01/09/2025] [Indexed: 01/23/2025] Open
Abstract
Nasopharyngeal carcinoma (NPC), a malignancy highly prevalent in East and Southeast Asia, is primarily treated with radiotherapy (RT). However, hypoxia-induced radioresistance presents a significant challenge. Nanozymes, nanomaterials with catalase-like activity, have emerged as a promising strategy for radiosensitization by converting elevated hydrogen peroxide in the tumor microenvironment into oxygen. Despite their potential, effectively targeting hypoxic lesions has been difficult. Here, we identify transferrin receptor 1 (TfR1) as an upregulated target in NPC, with its expression levels positively correlated with hypoxia. Human heavy-chain ferritin, a specific ligand of TfR1, selectively recognizes hypoxic NPC lesions in preclinical models. Based on these findings, we design a hypoxia-targeted nanozyme by loading platinum nanoparticles into ferritin. This nanozyme exhibits enhanced catalase-like activity and effectively alleviates tumor hypoxia in NPC xenografts. When combined with RT, a single injection of the nanozyme significantly inhibits tumor growth and prolongs mouse survival, outperforming sodium glycididazole, a clinically used radiosensitizer. In summary, our findings highlight TfR1 as an accessible cell surface target in hypoxic NPC lesions. The nanozyme targeting TfR1 holds promise for enhancing the therapeutic effectiveness of RT in NPC through an in situ oxygen-generation mechanism.
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Affiliation(s)
- Ruofei Zhang
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Yanfang Shen
- Department of Nuclear Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Xiaoying Zhou
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment, Guangxi Medical University, Ministry of Education, Nanning, China
| | - Jianru Li
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
| | - Hanqing Zhao
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
| | - Zixia Zhang
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
| | - Jun Zhao
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment, Guangxi Medical University, Ministry of Education, Nanning, China
| | - Hongjun Jin
- Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Shuanshuan Guo
- Cancer Center, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China
| | - Hui Ding
- Shenzhen Key Laboratory of nanozymes and Translational Cancer Research, Shenzhen Second People's Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Guohui Nie
- Shenzhen Key Laboratory of nanozymes and Translational Cancer Research, Shenzhen Second People's Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Zhe Zhang
- Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China.
| | - Ying Wang
- Department of Nuclear Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
| | - Xiyun Yan
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
- University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
- Nanozyme Laboratory in Zhongyuan, Henan Academy of Innovations in Medical Science, Zhengzhou, Henan, China.
| | - Kelong Fan
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
- University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
- Nanozyme Laboratory in Zhongyuan, Henan Academy of Innovations in Medical Science, Zhengzhou, Henan, China.
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Zhang Y, Lu Y, Xu Y, Le Z, Liu Y, Tu W, Liu Y. Hypoxia-induced degradation of PICK1 by RBCK1 promotes the proliferation of nasopharyngeal carcinoma cells. Life Sci 2023; 321:121594. [PMID: 36934971 DOI: 10.1016/j.lfs.2023.121594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/03/2023] [Accepted: 03/14/2023] [Indexed: 03/19/2023]
Abstract
AIMS Hypoxia is an important feature of nasopharyngeal carcinoma (NPC). "Protein interacting with PRKCA 1" (PICK1) is commonly downregulated in human malignancies and is functionally related to poor prognosis. However, there is a limited understanding of the upstream mechanisms regulating PICK1 currently. MAIN METHODS PICK1 and HIF-1α expression levels were analyzed by Immunohistochemistry (IHC), western blotting, and quantitative real-time PCR assay. Protein stability and ubiquitin assays were used to investigate PICK1 protein degradation. Immunofluorescence and co-immunoprecipitation assays were used to demonstrate the interaction between RBCK1 and PICK1. Gene knockdown by siRNA transfection was used to investigate the role of HIF-1α and RBCK1 in hypoxia-induced PICK1 degradation. Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) assays and subcutaneous xenograft nude models were used to explore the roles of RBCK1 and PICK1 in NPC cell proliferation. KEY FINDINGS PICK1 expression in NPC tissue was negatively relative to that of HIF-1α. HIF-1α downregulated PICK1 expression by facilitating its ubiquitination by the E3 ligases RANBP2-type and C3HC4-type zinc finger containing 1 (RBCK1), thereby enhancing proteasome-mediated PICK1 degradation. RBCK1 knockdown inhibited NPC cell proliferation, which was ameliorated by double knockdown of RBCK1/PICK1. SIGNIFICANCE These data provide evidence for an NPC cell adaptation mechanism to hypoxia, where HIF-1α regulates RBCK1, which targets PICK1 for degradation to promote cell proliferation.
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Affiliation(s)
- Yingzi Zhang
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Yue Lu
- Department of Radiotherapy, Huangpu Branch of the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Yiqing Xu
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Ziyu Le
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Yi Liu
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Wenzhi Tu
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
| | - Yong Liu
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
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PET imaging of hypoxia and apoptosis. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00205-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Marcus C, Sheikhbahaei S, Shivamurthy VKN, Avey G, Subramaniam RM. PET Imaging for Head and Neck Cancers. Radiol Clin North Am 2021; 59:773-788. [PMID: 34392918 DOI: 10.1016/j.rcl.2021.05.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Head and neck cancers are commonly encountered cancers in clinical practice in the United States. Fluorine-18-fluorodeoxyglucose (18F-FDG) PET/CT has been clinically applied in staging, occult primary tumor detection, treatment planning, response assessment, follow-up, recurrent disease detection, and prognosis prediction in these patients. Alternative PET tracers remain investigational and can provide additional valuable information such as radioresistant tumor hypoxia. The recent introduction of 18F-FDG PET/MR imaging has provided the advantage of combining the superior soft tissue resolution of MR imaging with the functional information provided by 18F-FDG PET. This article is a concise review of recent advances in PET imaging in head and neck cancer.
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Affiliation(s)
- Charles Marcus
- Department of Nuclear Medicine and Molecular Imaging, Emory University Hospital, Atlanta, GA, USA.
| | - Sara Sheikhbahaei
- Department of Radiology, Johns Hopkins Medical Institutions, 601 N. Caroline Street, JHOC 3235, Baltimore, MD 21287, USA
| | - Veeresh Kumar N Shivamurthy
- Epilepsy Center, St. Francis Hospital and Medical Center, Trinity Health of New England, 114 Woodland Street, Hartford, CT 06105, USA
| | - Greg Avey
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave #3284, Madison, WI 53792, USA
| | - Rathan M Subramaniam
- Dean's Office, Otago Medical School, University of Otago, 201 Great King Street, Dunedin 9016, New Zealand
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Zhao J, Liu D, Yang H, Yu S, He H. Long noncoding RNAs in head and neck squamous cell carcinoma: biological functions and mechanisms. Mol Biol Rep 2020; 47:8075-8090. [PMID: 32914266 DOI: 10.1007/s11033-020-05777-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 08/28/2020] [Indexed: 12/22/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the primary malignant tumor of the oral cavity, larynx, nasopharynx, esophagus and tongue. Although several novel therapeutic methods for HNSCC have been developed, the final therapeutic effect on the patient is still not satisfactory. Thus, it is imperative that scientists identify novel distinguishable markers with specific molecular characteristics that can be used in therapeutic and prognostic evaluation. Previous reports have shown that long noncoding RNAs (lncRNAs) are important regulators of gene expression in many cancers, including head and neck squamous cell carcinomas. Translational studies of lncRNAs in HNSCC are urgently required before their application as a treatment can be realized. We aimed to address the most relevant findings on lncRNAs as biomarkers or treatment targets in head and neck squamous cell carcinoma and to summarize their discovered pathways and mechanisms of action to reveal the possible future applications of these novel biomarkers in clinical translational research.
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Affiliation(s)
- Jiayu Zhao
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Daming Liu
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Hao Yang
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Shan Yu
- Department of Pathology, Second Affiliated Hospital of Harbin Medical University, No. 246 XueFu Avenue, Harbin, 150086, Heilongjiang, China.
| | - Hongjiang He
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, 150081, Heilongjiang, China.
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Abstract
Head and neck cancers are commonly encountered malignancies in the United States, of which the majority are attributed to squamous cell carcinoma. 18F-FDG-PET/CT has been well established in the evaluation, treatment planning, prognostic implications of these tumors and is routinely applied for the management of patients with these cancers. Many alternative investigational PET radiotracers have been extensively studied in the evaluation of these tumors. Although these radiotracers have not been able to replace 18F-FDG-PET/CT in routine clinical practice currently, they may provide important additional information about the biological mechanisms of these tumors, such as foci of tumor hypoxia as seen on hypoxia specific PET radiotracers such as 18F-Fluoromisonidazole (18F-FMISO), which could be useful in targeting radioresistant hypoxic tumor foci when treatment planning. There are multiple other hypoxia-specific PET radiotracers such as 18F-Fluoroazomycinarabinoside (FAZA), 18F-Flortanidazole (HX4), which have been evaluated similarly, of which 18F-Fluoromisonidazole (18F-FMISO) has been the most investigated. Other radiotracers frequently studied in the evaluation of these tumors include radiolabeled amino acid PET radiotracers, which show increased uptake in tumor cells with limited uptake in inflammatory tissue, which can be useful especially in differentiating postradiation inflammation from residual and/or recurrent disease. 18F-Fluorothymidine (FLT) is localized intracellularly by nucleoside transport and undergoes phosphorylation thereby being retained within tumor cells and can serve as an indicator of tumor proliferation. Decrease in radiotracer activity following treatment can be an early indicator of treatment response. This review aims at synthesizing the available literature on the most studied non-FDG-PET/CT in head and neck cancer.
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Affiliation(s)
- Charles Marcus
- Department of Radiology, West Virginia University, Morgantown, WV.
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The lncRNA PVT1 regulates nasopharyngeal carcinoma cell proliferation via activating the KAT2A acetyltransferase and stabilizing HIF-1α. Cell Death Differ 2019; 27:695-710. [PMID: 31320749 PMCID: PMC7206084 DOI: 10.1038/s41418-019-0381-y] [Citation(s) in RCA: 150] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 06/13/2019] [Accepted: 06/19/2019] [Indexed: 12/11/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) play important roles in regulating the development and progression of many cancers. However, the clinical significance of specific lncRNAs in the context of nasopharyngeal carcinoma (NPC) and the molecular mechanisms by which they regulate this form of cancer remain largely unclear. In this study we found that the lncRNA PVT1 was upregulated in NPC, and that in patients this upregulation was associated with reduced survival. RNA sequencing revealed that PVT1 was responsible for regulating NPC cell proliferation and for controlling a hypoxia-related phenotype in these cells. PVT1 knockdown reduced NPC cell proliferation, colony formation, and tumorigenesis in a subcutaneous mouse xenograft model systems. We further found that PVT1 serves as a scaffold for the chromatin modification factor KAT2A, which mediates histone 3 lysine 9 acetylation (H3K9), recruiting the nuclear receptor binding protein TIF1β to activate NF90 transcription, thereby increasing HIF-1α stability and promoting a malignant phenotype in NPC cells. Overexpression of NF90 or HIF-1α restored the proliferation in cells that had ceased proliferating due to PVT1 or KAT2A depletion. Conversely, overexpression of active KAT2A or TIF1β, but not of KAT2A acetyltransferase activity-deficient mutants or TIF1β isoforms lacking H3K9ac binding sites, promoted a PVT1-mediated increase in NF90 transcription, as well as increased HIF-1α stability and cell proliferation. PVT1 knockdown enhanced the radiosensitization effect in NPC cells via inhibiting binding between H3K9ac and TIF1β in a manner. Taken together, our results demonstrate that PVT1 serves an oncogenic role and plays an important role in radiosensitivity in malignant NPC via activating the KAT2A acetyltransferase and stabilizing HIF-1α.
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10
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Wen X, Liu X, Mao YP, Yang XJ, Wang YQ, Zhang PP, Lei Y, Hong XH, He QM, Ma J, Liu N, Li YQ. Long non-coding RNA DANCR stabilizes HIF-1α and promotes metastasis by interacting with NF90/NF45 complex in nasopharyngeal carcinoma. Theranostics 2018; 8:5676-5689. [PMID: 30555573 PMCID: PMC6276287 DOI: 10.7150/thno.28538] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Accepted: 10/17/2018] [Indexed: 02/07/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) play an important role in the development and progression of cancers. However, the clinical significances of lncRNAs and their functions and mechanisms in nasopharyngeal carcinoma (NPC) remain largely unclear. Methods: Quantitative RT-PCR was used to determine DANCR expression and Kaplan-Meier curves were used to evaluate its prognostic value. RNA sequencing followed by bioinformatic analysis was performed to determine the potential function of DANCR. In vitro and in vivo experiments were conducted to investigate its biological effects. DANCR-interacting proteins were identified by RNA pull-down assay followed by mass spectrometry and western blotting, and then confirmed by RNA immunoprecipitation (RIP) assays. Results: Our previous microarray analysis identified a metastasis-associated lncRNA DANCR. Here, we found that DANCR was upregulated in NPC, especially in those with lymph lode metastasis, and its upregulation could predict poor survival. We then constructed a prognostic predictive model. RNA sequencing followed by bioinformatic analysis revealed that DANCR was responsible for NPC metastasis and hypoxia phenotype. Functional studies showed that DANCR promoted NPC cell invasion and metastasis in vitro and in vivo. Further investigation suggested that DANCR could increase HIF-1α mRNA stability through interacting with the NF90/NF45 complex. Additionally, overexpression of HIF-1α in DANCR knockdown cells restored its suppressive effects on NPC cell migration and invasion. Conclusions: Taken together, our results suggest that DANCR acts as a prognostic biomarker and increases HIF-1α mRNA stability by interacting with NF90/NF45, leading to metastasis and disease progression of NPC.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Jun Ma
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, No. 651 Dongfeng Road East, Guangzhou 510060, People's Republic of China
| | - Na Liu
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, No. 651 Dongfeng Road East, Guangzhou 510060, People's Republic of China
| | - Ying-Qin Li
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, No. 651 Dongfeng Road East, Guangzhou 510060, People's Republic of China
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11
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You B, Shan Y, Bao L, Chen J, Yang L, Zhang Q, Zhang W, Zhang Z, Zhang J, Shi S, You Y. The biology and function of extracellular vesicles in nasopharyngeal carcinoma (Review). Int J Oncol 2017; 52:38-46. [PMID: 29138808 DOI: 10.3892/ijo.2017.4202] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2017] [Accepted: 10/02/2017] [Indexed: 11/06/2022] Open
Abstract
Extracellular vesicles are a heterogeneous group of membrane-enclosed vesicles, which play an important role in intercellular communication. Increasing number of studies have shown that tumor-derived extracellular vesicles might be involved in the transfer of oncogenic cargo (proteins, lipids, messenger RNA, microRNA, non-coding RNAs and DNA) through which cancer cells could shape the tumor microenvironment and influence tumor progression. Nasopharyngeal carcinoma-derived extracellular vesicles have also reported to facilitate tumor proliferation, metastasis and immune escape. Moreover, nasopharyngeal carcinoma-derived extracellular vesicles might serve as biomarkers for early diagnosis and therapeutic targets. The present review provides information on the biological and clinical significance of extracellular vesicles in tumors, especially in nasopharyngeal carcinoma.
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Affiliation(s)
- Bo You
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Ying Shan
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Lili Bao
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Jing Chen
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Liu Yang
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Qicheng Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Wei Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Zhenxin Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Jie Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Si Shi
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Yiwen You
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
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12
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Liang SB, Wang Y, Hu XF, He SS, Yang XL, Liu LZ, Cui CY, Chen Y, Fu LW. Survival and Toxicities of IMRT Based on the RTOG Protocols in Patients with Nasopharyngeal Carcinoma from the Endemic Regions of China. J Cancer 2017; 8:3718-3724. [PMID: 29151959 PMCID: PMC5688925 DOI: 10.7150/jca.20351] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 08/04/2017] [Indexed: 11/05/2022] Open
Abstract
Background: This study evaluated the survival outcomes and toxicities of intensity-modulated radiation therapy (IMRT) based on the RTOG 0225/0615 RT protocols in patients with nasopharyngeal carcinoma (NPC) from a region of China where this tumor type is endemic. Methods: A total of 455 patients with non-metastatic, histologically-confirmed NPC were retrospectively reviewed. All patients were treated by IMRT using the RTOG 0225/0615 RT protocols; 91.1% (288/316) of patients with stage III-IVb NPC received concurrent chemotherapy +/- induction chemotherapy or adjuvant chemotherapy. Results: Estimated four-year overall survival (OS), failure free survival (FFS), local relapse free survival (LRFS), regional relapse free survival (RRFS) and distant metastasis free survival (DMFS) were 83.8%, 80.5%, 94.3%, 96.7% and 85.8%, respectively. T and N category were significant prognostic factors for OS, FFS, RRFS and DMFS; and T category, for LRFS. In-field failure was the major loco-regional failure pattern. During RT, 206 (45.3%) patients experienced acute grade 3-4 toxicities. The most common acute toxicity was mucositis; 124 (27.2%) patients experienced grade 3-4 mucositis; 46 (10.1%) experienced serious late toxicities. The most common late toxicity was MRI-detected radiation-induced temporal lobe necrosis (6.8%). Conclusions: The RTOG IMRT protocols are feasible for patients with NPC from the endemic regions of China.
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Affiliation(s)
- Shao-Bo Liang
- Department of Radiation Oncology, Cancer Center, First People's Hospital of Foshan Affiliated to Sun Yat-sen University, Foshan 528000, China.,Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Yan Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xue-Feng Hu
- Department of Radiation Oncology, Cancer Center, First People's Hospital of Foshan Affiliated to Sun Yat-sen University, Foshan 528000, China
| | - Sha-Sha He
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Xing-Li Yang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Li-Zhi Liu
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Chun-Yan Cui
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Yong Chen
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Li-Wu Fu
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
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13
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Qiu J, Lv B, Fu M, Wang X, Zheng X, Zhuo W. 18 F-Fluoromisonidazole positron emission tomography/CT-guided volumetric-modulated arc therapy-based dose escalation for hypoxic subvolume in nasopharyngeal carcinomas: A feasibility study. Head Neck 2017; 39:2519-2527. [PMID: 28963789 DOI: 10.1002/hed.24925] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 04/26/2017] [Accepted: 07/17/2017] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND The purpose of this study is to investigate the feasibility of a simultaneously integrated boost to the hypoxic subvolume of nasopharyngeal carcinomas (NCPs) under the guidance of 18 F-fluoromisonidazole (FMISO) positron emission tomography (PET)/CT using volumetric-modulated arc therapy (VMAT) and intensity-modulated radiotherapy (IMRT) techniques. METHODS Eight patients with NPC were treated with simultaneous integrated boost-IMRT (treatment plan named IMRT70) with dose prescriptions of 70 Gy, 66 Gy, 60 Gy, and 54 Gy to the gross tumor volume (GTV), positive neck nodes, the planning target volume (PTV), and the clinically negative neck, respectively. Based on the same datasets, experimental plans with the same dose prescription plus a dose boost of 14 Gy (an escalation of 20% of the prescription dose) to the hypoxic volume target contoured on the pretreatment 18 F-FMISO PET/CT imaging were generated using IMRT and VMAT techniques, respectively (represented by IMRT84 and VMAT84). Two or more arcs (approximately 2-2.5 arcs, totally rotating angle <1000 degrees) were used in VMAT plans and 9 equally separated fields in IMRT plans. Dosimetric parameters, total monitor units, and delivery time were calculated for comparative study of plan quality and delivery efficiency between IMRT84 and VMAT84. RESULTS In experimental plans, hypoxic target volumes successfully received the prescribed dose of 84 Gy in compliance with other dose constraints with either the IMRT technique or the VMAT technique. In terms of the target coverage, dose homogeneity, and organs at risk (OAR) sparing, there was no statistically significant difference between the actual treatment plan of IMRT70 and experimental plans. The total monitor unit of VMAT84 (525.7 ± 39.8) was significantly less than IMRT70 (1171.5 ± 167; P = .001) and IMRT84 (1388.3 ± 151.0; P = .001) per fraction, with 55.1% and 62.1% reduction. The average machine delivery time was 3.5 minutes for VMAT plans in comparison with approximately 8 minutes for IMRT plans, resulting in a reduction factor of 56.2%. For experimental plans, the 3D gamma index average was over 98.0% with no statistical significant difference when a 3%/3 mm gamma passing rate criteria was used. CONCLUSION With the guidance of 18 F-FMISO PET/CT imaging, dose escalation to hypoxic zones within NPC could be achieved and delivered efficiently with the VMAT technique in comparison with the IMRT technique.
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Affiliation(s)
- Jianjian Qiu
- Institute of Radiation Medicine, Fudan University, Shanghai, China
| | - Bo Lv
- Department of Radiation Oncology, Fudan University Huadong Hospital, Shanghai, China
| | - Meina Fu
- Department of Radiation Oncology, Fudan University Huadong Hospital, Shanghai, China
| | - Xianglian Wang
- Department of Radiation Oncology, Fudan University Huadong Hospital, Shanghai, China
| | - Xiangpeng Zheng
- Department of Radiation Oncology, Fudan University Huadong Hospital, Shanghai, China
| | - Weihai Zhuo
- Institute of Radiation Medicine, Fudan University, Shanghai, China
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14
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Nishikawa Y, Yasuda K, Okamoto S, Ito YM, Onimaru R, Shiga T, Tsuchiya K, Watanabe S, Takeuchi W, Kuge Y, Peng H, Tamaki N, Shirato H. Local relapse of nasopharyngeal cancer and Voxel-based analysis of FMISO uptake using PET with semiconductor detectors. Radiat Oncol 2017; 12:148. [PMID: 28877734 PMCID: PMC5586018 DOI: 10.1186/s13014-017-0886-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2017] [Accepted: 09/01/2017] [Indexed: 12/02/2022] Open
Abstract
Background Hypoxic cancer cells are thought to be radioresistant and could impact local recurrence after radiotherapy (RT). One of the major hypoxic imaging modalities is [18F]fluoromisonidazole positron emission tomography (FMISO-PET). High FMISO uptake before RT could indicate radioresistant sites and might be associated with future local recurrence. The predictive value of FMISO-PET for intra-tumoral recurrence regions was evaluated using high-resolution semiconductor detectors in patients with nasopharyngeal carcinoma after intensity-modulated radiotherapy (IMRT). Methods Nine patients with local recurrence and 12 patients without local recurrence for more than 3 years were included in this study. These patients received homogeneous and standard doses of radiation to the primary tumor irrespective of FMISO uptake. The FMISO-PET image before RT was examined via a voxel-based analysis, which focused on the relationship between the degree of FMISO uptake and recurrence region. Results In the pretreatment FMISO-PET images, the tumor-to-muscle ratio (TMR) of FMISO in the voxels of the tumor recurrence region was significantly higher than that of the non-recurrence region (p < 0.0001). In the recurrent patient group, a TMR value of 1.37 (95% CI: 1.36–1.39) corresponded to a recurrence rate of 30%, the odds ratio was 5.18 (4.87–5.51), and the area under the curve (AUC) of the receiver operating characteristic curve was 0.613. In all 21 patients, a TMR value of 2.42 (2.36–2.49) corresponded to an estimated recurrence rate of 30%, and the AUC was only 0.591. Conclusions The uptake of FMISO in the recurrent region was significantly higher than that in the non-recurrent region. However, the predictive value of FMISO-PET before IMRT is not sufficient for up-front dose escalation for the intra-tumoral high-uptake region of FMISO. Because of the higher mean TMR of the recurrence region, a new hypoxic imaging method is needed to improve the sensitivity and specificity for hypoxia. Electronic supplementary material The online version of this article doi: (10.1186/s13014-017-0886-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yukiko Nishikawa
- Department of Radiation Medicine, Graduate School of Medicine, Hokkaido University, North-15 West-7, Sapporo, Japan
| | - Koichi Yasuda
- Department of Radiation Medicine, Graduate School of Medicine, Hokkaido University, North-15 West-7, Sapporo, Japan. .,Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education, Sapporo, Japan.
| | - Shozo Okamoto
- Department of Nuclear Medicine, Graduate School of Medicine, Sapporo, Japan
| | - Yoichi M Ito
- Department of Biostatistics, Graduate School of Medicine, Sapporo, Japan
| | - Rikiya Onimaru
- Department of Radiation Medicine, Graduate School of Medicine, Hokkaido University, North-15 West-7, Sapporo, Japan
| | - Tohru Shiga
- Department of Nuclear Medicine, Graduate School of Medicine, Sapporo, Japan
| | - Kazuhiko Tsuchiya
- Department of Radiation Medicine, Graduate School of Medicine, Hokkaido University, North-15 West-7, Sapporo, Japan
| | - Shiro Watanabe
- Department of Nuclear Medicine, Graduate School of Medicine, Sapporo, Japan
| | - Wataru Takeuchi
- Research & Development Group, Hitachi, Ltd., Kokubunji, Tokyo, Japan
| | - Yuji Kuge
- Central Institute of Isotope Science, Hokkaido University, Sapporo, Japan
| | - Hao Peng
- Stanford University, Stanford, CA, USA
| | - Nagara Tamaki
- Department of Nuclear Medicine, Graduate School of Medicine, Sapporo, Japan
| | - Hiroki Shirato
- Department of Radiation Medicine, Graduate School of Medicine, Hokkaido University, North-15 West-7, Sapporo, Japan.,Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education, Sapporo, Japan
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15
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Liu H, Jiang F, Jia X, Lan J, Guo H, Li E, Yan A, Wang Y. Cycling hypoxia affects cell invasion and proliferation through direct regulation of claudin1 / claudin7 expression, and indirect regulation of P18 through claudin7. Oncotarget 2016; 8:10298-10311. [PMID: 28055967 PMCID: PMC5354660 DOI: 10.18632/oncotarget.14397] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 12/05/2016] [Indexed: 12/25/2022] Open
Abstract
Claudins (CLDNs), the major integral membrane proteins at tight junction, play critical roles in apical cell-to-cell adhesion, maintenance of epithelial polarity, and formation of impermeable barriers between epithelial cells.We investigated in this study the expression of CLDNs- Claudin1 (CLDN1) and Claudin7 (CLDN7), and their relation to tumor progression in nasopharyngeal cancer (NPC). CLDN7, rather than CLDN1, showed higher expression in both undifferentiated tumor tissue and the poorly differentiated CNE2 cells, compared with differentiated tissue and the highly differentiated CNE1 cells. Furthermore, knockdown of CLDN7 dramatically inhibited the metastasis and invasion of CNE2 cells suggesting that CLDN7 could act as a biomarker for NPC metastasis.Cycling hypoxia could induce significant changes in CLDN1 and CLDN7 expression in NPC cells. Genetics analysis demonstrated that CLDN1/CLDN7 were not only regulated directly by HIF1a but also affected each other through a feedback mechanism. CLDN7 acted as a bridge to promote HIF1a-induced P18 expression and cell differentiation. Taken together, our results provide evidence that adjusting the oxygenation time and cycles in NPC might be an effective method to prevent / delay the metastasis of poorly differentiated NPC cells.
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Affiliation(s)
- Hong Liu
- 1 Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Feifei Jiang
- 1 Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Xinshan Jia
- 2 Department of Pathology, China Medical University, Shenyang, Liaoning 110001, China
| | - Jing Lan
- 3 Department of Dermatology, China Medical University, Shenyang, Liaoning 110001, China
| | - Hao Guo
- 3 Department of Dermatology, China Medical University, Shenyang, Liaoning 110001, China
| | - Erran Li
- 4 Institute of Respiratory Disease, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Aihui Yan
- 1 Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Yan Wang
- 1 Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
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16
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Taylor E, Yeung I, Keller H, Wouters BG, Milosevic M, Hedley DW, Jaffray DA. Quantifying hypoxia in human cancers using static PET imaging. Phys Med Biol 2016; 61:7957-7974. [PMID: 27779123 DOI: 10.1088/0031-9155/61/22/7957] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Compared to FDG, the signal of 18F-labelled hypoxia-sensitive tracers in tumours is low. This means that in addition to the presence of hypoxic cells, transport properties contribute significantly to the uptake signal in static PET images. This sensitivity to transport must be minimized in order for static PET to provide a reliable standard for hypoxia quantification. A dynamic compartmental model based on a reaction-diffusion formalism was developed to interpret tracer pharmacokinetics and applied to static images of FAZA in twenty patients with pancreatic cancer. We use our model to identify tumour properties-well-perfused without substantial necrosis or partitioning-for which static PET images can reliably quantify hypoxia. Normalizing the measured activity in a tumour voxel by the value in blood leads to a reduction in the sensitivity to variations in 'inter-corporal' transport properties-blood volume and clearance rate-as well as imaging study protocols. Normalization thus enhances the correlation between static PET images and the FAZA binding rate K 3, a quantity which quantifies hypoxia in a biologically significant way. The ratio of FAZA uptake in spinal muscle and blood can vary substantially across patients due to long muscle equilibration times. Normalized static PET images of hypoxia-sensitive tracers can reliably quantify hypoxia for homogeneously well-perfused tumours with minimal tissue partitioning. The ideal normalizing reference tissue is blood, either drawn from the patient before PET scanning or imaged using PET. If blood is not available, uniform, homogeneously well-perfused muscle can be used. For tumours that are not homogeneously well-perfused or for which partitioning is significant, only an analysis of dynamic PET scans can reliably quantify hypoxia.
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Affiliation(s)
- Edward Taylor
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Techna Institute, University Health Network, Toronto, Canada
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17
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Rajendran JG, Krohn KA. F-18 fluoromisonidazole for imaging tumor hypoxia: imaging the microenvironment for personalized cancer therapy. Semin Nucl Med 2015; 45:151-62. [PMID: 25704387 DOI: 10.1053/j.semnuclmed.2014.10.006] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hypoxia in solid tumors is one of the seminal mechanisms for developing aggressive trait and treatment resistance in solid tumors. This evolutionarily conserved biological mechanism along with derepression of cellular functions in cancer, although resulting in many challenges, provide us with opportunities to use these adversities to our advantage. Our ability to use molecular imaging to characterize therapeutic targets such as hypoxia and apply this information for therapeutic interventions is growing rapidly. Evaluation of hypoxia and its biological ramifications to effectively plan appropriate therapy that can overcome the cure-limiting effects of hypoxia provides an objective means for treatment selection and planning. Fluoromisonidazole (FMISO) continues to be the lead radiopharmaceutical in PET imaging for the evaluation, prognostication, and quantification of tumor hypoxia, one of the key elements of the tumor microenvironment. FMISO is less confounded by blood flow, and although the images have less contrast than FDG-PET, its uptake after 2 hours is an accurate reflection of inadequate regional oxygen partial pressure at the time of radiopharmaceutical administration. By virtue of extensive clinical utilization, FMISO remains the lead candidate for imaging and quantifying hypoxia. The past decade has seen significant technological advances in investigating hypoxia imaging in radiation treatment planning and in providing us with the ability to individualize radiation delivery and target volume coverage. The presence of widespread hypoxia in the tumor can be effectively targeted with a systemic hypoxic cell cytotoxin or other agents that are more effective with diminished oxygen partial pressure, either alone or in combination. Molecular imaging in general and hypoxia imaging in particular will likely become an important in vivo imaging biomarker of the future, complementing the traditional direct tissue sampling methods by providing a snap shot of a primary tumor and metastatic disease and in following treatment response and will serve as adjuncts to personalized therapy.
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Affiliation(s)
- Joseph G Rajendran
- Department of Radiology, University of Washington, Seattle, WA; Department of Radiation Oncology, University of Washington, Seattle, WA.
| | - Kenneth A Krohn
- Department of Radiology, University of Washington, Seattle, WA; Department of Radiation Oncology, University of Washington, Seattle, WA
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18
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The natural compound gambogic acid radiosensitizes nasopharyngeal carcinoma cells under hypoxic conditions. TUMORI JOURNAL 2015; 102:135-43. [PMID: 26357974 DOI: 10.5301/tj.5000411] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2015] [Indexed: 12/19/2022]
Abstract
AIMS Hypoxia is an important factor that causes decreased local disease control as well as increased distant metastases and resistance to radiotherapy in patients with advanced nasopharyngeal carcinoma (NPC). Gambogic acid (GA), the major active ingredient of gamboge, exerts antitumor effects in vitro and in vivo. However, the molecular mechanism by which GA inhibits tumor radioresistance remains unclear. The present study aimed to investigate the radiosensitizing effects of GA on NPC and explore the underlying mechanisms. MATERIALS AND METHODS CNE-1 and CNE-2 cells exposed to hypoxia and radiation were treated with GA at different concentrations. CCK-8 assay, clonogenic assay, and flow cytometry were performed to analyze cell proliferation, colony formation, apoptosis, and cell cycle. The expression levels of hypoxia-inducible factor-1α (HIF-1α), Bcl-2, Bax, caspase-3, cyclin B1/p-cdc2 and γ-H2AX were assessed using Western blot and/or immunofluorescence analysis. RESULTS Results of the CCK-8 assay, clonogenic assay, and flow cytometry showed that treatment of NPC cells with growth-suppressive concentrations of GA resulted in G2/M phase arrest and apoptosis. Western blot analysis demonstrated that GA-induced cell cycle arrest and apoptosis in CNE-2 cells was associated with upregulated expression of caspase-3 and Bax and downregulated expression of Bcl-2 and cyclin B1/p-cdc2 in hypoxia. Treatment with GA markedly decreased the expression of HIF-1α under hypoxic conditions. CONCLUSIONS The results of this study suggest that GA efficiently radiosensitizes NPC cells and the effect may be significant in hypoxic conditions.
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19
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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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20
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Pan WL, Wong JH, Fang EF, Chan YS, Ng TB, Cheung RCF. Preferential cytotoxicity of the type I ribosome inactivating protein alpha-momorcharin on human nasopharyngeal carcinoma cells under normoxia and hypoxia. Biochem Pharmacol 2014; 89:329-39. [PMID: 24637239 PMCID: PMC5937121 DOI: 10.1016/j.bcp.2014.03.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Revised: 03/06/2014] [Accepted: 03/07/2014] [Indexed: 10/25/2022]
Abstract
All primary nasopharyngeal carcinoma (NPC) tumors contain hypoxic regions which are implicated in decreased local control and increased distant metastases, as well as resistance to chemotherapy in advanced NPC patients. One of the promising therapeutic approaches for NPC is to use drugs that can target hypoxic factors in tumors. In the present investigation, the type I ribosome inactivating protein α-momorcharin (α-MMC), isolated from seeds of the bitter gourd Momordica charantia, reduced cell viability and inhibited clonogenic formation of human NPC CNE2 and HONE1 cells under normoxia and cobalt chloride-induced hypoxia. By comparison, α-MMC exhibited only slight cytotoxicity on human nasopharyngeal epithelial NP69 cells under normoxia. Interestingly, α-MMC suppressed the expression levels of hypoxia-inducible factor 1-alpha (HIF1α) and vascular endothelial growth factor (VEGF) in hypoxic NPC, as well as the growth of human umbilical vein endothelial cells. Further study disclosed that α-MMC targeted endoplasmic reticulum and down-regulated unfolded protein response (UPR) in NPC cells. Moreover, α-MMC induced apoptosis in NPC cells in a dose- and time-dependent manner. It initiated mitochondrial- and death receptor-mediated apoptotic signaling in CNE2 cells, but there was hardly any effect on HONE1 cells. In addition, α-MMC brought about G0/G1 phase cell cycle arrest in CNE2 cells and S phase arrest in HONE1 cells. Collectively, α-MMC preferentially exhibited inhibitory effect on normoxic and hypoxic NPC cells partly by blocking survival signaling (e.g. HIF1α, VEGF and UPR), and triggering apoptotic pathways mediated by mitochondria or death receptor. These observations indicate the potential utility of α-MMC for prophylaxis and therapy of NPC.
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Affiliation(s)
- Wen Liang Pan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Jack Ho Wong
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Evandro Fei Fang
- National Institute on Ageing, National Institutes of Health, Baltimore, MD, USA
| | - Yau Sang Chan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Tzi Bun Ng
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
| | - Randy Chi Fai Cheung
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
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21
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Translational research in nasopharyngeal carcinoma. Oral Oncol 2014; 50:345-52. [DOI: 10.1016/j.oraloncology.2013.11.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 11/11/2013] [Accepted: 11/13/2013] [Indexed: 11/20/2022]
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Cheng J, Lei L, Xu J, Sun Y, Zhang Y, Wang X, Pan L, Shao Z, Zhang Y, Liu G. 18F-fluoromisonidazole PET/CT: a potential tool for predicting primary endocrine therapy resistance in breast cancer. J Nucl Med 2013; 54:333-40. [PMID: 23401605 DOI: 10.2967/jnumed.112.111963] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
UNLABELLED Although endocrine therapy is an effective method to treat estrogen receptor (ER)-positive breast cancer, approximately 30%-40% of all hormone receptor-positive tumors display de novo resistance. The aim of our current study was to analyze whether (18)F-labeled fluoromisonidazole (1-(2-nitro-1-imidazolyl)-2-hydroxy-3-fluoropropane [(18)F-FMISO]) PET/CT could predict primary resistance to hormonal therapy in ER-positive breast cancer. METHODS Postmenopausal women who had ER-α-positive breast cancer, stages II-IV, and had never received prior endocrine therapy were prospectively enrolled in this study. Patients underwent both (18)F-FDG and (18)F-FMISO PET/CT scans before and after treatment. The hottest (18)F-FDG standardized uptake value (SUV) in the tumor foci, the SUVs at 2 and 4 h, and the TBR2 h and TBR4 h for the target lesions were calculated (TBR2 h = SUV2 hT/SUV2 hB and TBR4 h = SUV4 hT/SUV4 hB [TBR is the tumor-to-background ratio]). Clinical outcomes of primary endocrine therapy with letrozole were evaluated according to the criteria of the World Health Organization after at least 3 mo of treatment. Immunohistochemistry for markers of proliferation (Ki67) and hypoxia-induced factor 1α was performed on a subset of tumors that had undergone biopsy or surgery. Pearson and Spearman analysis was used to determine the correlation between the parameters of (18)F-FDG and (18)F-FMISO uptake and clinical or immunohistochemistry outcomes with a 0.01 threshold for statistical significance. RESULTS A total of 45 lesions (13 primary, 32 metastatic) from 20 patients met the inclusion criteria in this study. Baseline (18)F-FDG and (18)F-FMISO PET/CT scans were obtained for 33 lesions from 16 patients. The correlation between baseline (18)F-FDG uptake and clinical outcome was weak and did not reach statistical significance (r = 0.37, P = 0.031). However, there was a significantly positive correlation between baseline (18)F-FMISO uptake (SUV2 hT, TBR2 h, SUV4 hT, and TBR4 h) and clinical outcomes after ≥3 mo of primary endocrine therapy with letrozole (r = 0.77, 0.76, 0.71, and 0.78, respectively; P < 0.0001). The application of a TBR4 h cutoff of ≥1.2 allowed the prediction of 88% of the cases of progressive disease (15/17). Despite poor correlation between (18)F-FMISO uptake and hypoxia-induced factor 1α expression, a marginal positive correlation between TBR4 h and Ki67 expression was measured (r = 0.51, P = 0.011) in a subset of malignant lesions acquired by biopsy or surgery. CONCLUSION (18)F-FMISO PET/CT can be used to predict primary endocrine resistance in ER-positive breast cancer.
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Affiliation(s)
- Jingyi Cheng
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
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Yasuda K, Onimaru R, Okamoto S, Shiga T, Katoh N, Tsuchiya K, Suzuki R, Takeuchi W, Kuge Y, Tamaki N, Shirato H. [18F]fluoromisonidazole and a New PET System With Semiconductor Detectors and a Depth of Interaction System for Intensity Modulated Radiation Therapy for Nasopharyngeal Cancer. Int J Radiat Oncol Biol Phys 2013; 85:142-7. [DOI: 10.1016/j.ijrobp.2012.03.029] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2011] [Revised: 02/04/2012] [Accepted: 03/10/2012] [Indexed: 10/27/2022]
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Hong B, Lui VWY, Hashiguchi M, Hui EP, Chan ATC. Targeting tumor hypoxia in nasopharyngeal carcinoma. Head Neck 2011; 35:133-45. [DOI: 10.1002/hed.21877] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2010] [Revised: 05/26/2011] [Accepted: 06/14/2011] [Indexed: 02/04/2023] Open
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Li L, Hu M, Zhu H, Zhao W, Yang G, Yu J. Comparison of 18F-Fluoroerythronitroimidazole and 18F-fluorodeoxyglucose positron emission tomography and prognostic value in locally advanced non-small-cell lung cancer. Clin Lung Cancer 2011; 11:335-40. [PMID: 20837459 DOI: 10.3816/clc.2010.n.042] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION The aim of this study was to compare glucose metabolism and hypoxia using 18F- fluorodeoxyglucose (18F-FDG) and 18F-fluoroerythronitroimidazole (18F-FETNIM) positron emission tomography (PET) and investigate their prognostic role on survival in patients with locally advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Twenty-six patients with NSCLC were imaged with 18F-FETNIM PET/computed tomography (CT), and 11 cases also with 18F-FDG PET/CT imaging among those with significant 18F-FETNIM uptake, a few days before any chemo/adiation therapy. The maximum standardized uptake value (SUVmax) was used to depict 18F-FDG uptake, and hypoxic volume (HV) and tumor:blood ratio (T/Bmax) were used to quantify hypoxia. Overall survival (OS) after treatment was selected as the endpoint of the study. RESULTS Twenty-two patients (84.6%) had significant 18F-FETNIM uptake in the primary tumor. The correlations between the overall tumor SUVmax of 18F-FDG and HV, T/Bmax ratio of 18F-FENTIM in 11 patients were small and without significant difference. In univariate analyses, log-rank tests were used to compare Kaplan-Meier survival curves. 18F-FETNIM T/Bmax ratio and HV were strong predictors for OS, and 18F-FDG uptake of the primary lesions did not have a significant relationship with survival. In multivariate survival analysis, only 18F-FETNIM T/Bmax ratio was found to be an independent prognostic factor. CONCLUSION Imaging using both 18F-FETNIM and 18F-FDG appears to be beneficial in the evaluation of solid tumors. 18F-FETNIM imaging provides us with a valuable method to detect tumor hypoxia and predict OS. These preliminary results warrant validation in larger trials.
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Affiliation(s)
- Ling Li
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, China
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Avanzo M, Stancanello J, Franchin G, Sartor G, Jena R, Drigo A, Dassie A, Gigante M, Capra E. Correlation of a hypoxia based tumor control model with observed local control rates in nasopharyngeal carcinoma treated with chemoradiotherapy. Med Phys 2010; 37:1533-44. [DOI: 10.1118/1.3352832] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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Contribution of hypoxia-measuring molecular imaging techniques to radiotherapy planning and treatment. Clin Transl Oncol 2010; 12:22-6. [DOI: 10.1007/s12094-010-0462-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Hypoxia-targeting by tirapazamine (TPZ) induces preferential growth inhibition of nasopharyngeal carcinoma cells with Chk1/2 activation. Invest New Drugs 2009; 29:401-10. [PMID: 20013349 DOI: 10.1007/s10637-009-9356-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2009] [Accepted: 11/09/2009] [Indexed: 01/29/2023]
Abstract
Hypoxia is commonly developed in solid tumors, which contributes to metastasis as well as radio- and chemo-resistance. Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic head and neck cancer prevalent in Southeast Asia with a high incidence rate of 15-30/100,000 persons/year (comparable to that of pancreatic cancer in the US). Previous clinical studies in NPC showed that hypoxia is detected in almost 100% of primary tumors and overexpression of hypoxia markers correlated with poor clinical outcome. Tirapazamine (TPZ) is a synthetic hypoxia-activated prodrug, which preferentially forms cytotoxic and DNA-damaging free radicals under hypoxia, thus selectively eradicate hypoxic cells. Here, we hypothesized that specific hypoxia-targeting by this clinical trial agent may be therapeutic for NPC. Our findings demonstrated that under hypoxia, TPZ was able to induce preferential growth inhibition of NPC cells, which was associated with marked cell cycle arrest at S-phase and PARP cleavage (a hallmark of apoptosis). Examination of S-phase checkpoint regulators revealed that Chk1 and Chk2 were selectively activated by TPZ in NPC cells under hypoxia. Hypoxia-selectivity of TPZ was also demonstrated by preferential downregulation of several important hypoxia-induced markers (HIF-1α, CA IX and VEGF) under hypoxia. Furthermore, we demonstrated that TPZ was equally effective and hypoxia-selective even in the presence of the EBV oncoprotein, LMP1 or the EBV genome. In summary, encouraging results from this proof-of-concept study implicate the therapeutic potential of hypoxia-targeting approaches for the treatment of NPC.
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Huchet A, Fernandez P, Allard M, Belkacémi Y, Maire JP, Trouette R, Eimer S, Tourdias T, Loiseau H. Imagerie moléculaire de l’hypoxie tumorale. Cancer Radiother 2009; 13:747-57. [DOI: 10.1016/j.canrad.2009.07.038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2008] [Revised: 06/05/2009] [Accepted: 07/08/2009] [Indexed: 12/28/2022]
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Xueguan L, Xiaoshen W, Yongsheng Z, Chaosu H, Chunying S, Yan F. Hypoxia inducible factor-1 alpha and vascular endothelial growth factor expression are associated with a poor prognosis in patients with nasopharyngeal carcinoma receiving radiotherapy with carbogen and nicotinamide. Clin Oncol (R Coll Radiol) 2008; 20:606-12. [PMID: 18692368 DOI: 10.1016/j.clon.2008.07.001] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2008] [Revised: 07/02/2008] [Accepted: 07/03/2008] [Indexed: 12/14/2022]
Abstract
AIMS Hypoxia reduces tumour radiosensitivity and hypoxia inducible factor-1 alpha (HIF-1 alpha) plays an important role in this process. The aim of the study was to assess the prognostic impact of HIF-1 alpha and vascular endothelial growth factor (VEGF) in patients with nasopharyngeal carcinoma who received radiation with hypoxia-modifying therapy (carbogen plus nicotinamide). MATERIALS AND METHODS The immunohistochemical expression of HIF-1 alpha and VEGF was evaluated in nasopharyngeal carcinoma biopsies from 59 patients who received conventional radiotherapy combined with carbogen and nicotinamide. RESULTS A significant positive association was found between HIF-1 alpha and VEGF expression (P = 0.003). There was no association found between the level of HIF-1 alpha, VEGF expression and tumour stage, nodal stage, or clinical stage. Kaplan-Meier plots showed that positive HIF-1 alpha and VEGF expression were associated with a higher distant metastasis, a worse overall and disease-free survival, and the level of HIF-1 alpha and VEGF expression had no effect on locoregional recurrence. The multivariate analysis failed to confirm any association between HIF-1 alpha or VEGF and metastasis, disease-free or overall survival. CONCLUSIONS These results suggest that the expression of hypoxia-associated markers (HIF-1 alpha and VEGF) may have prognostic significance in patients with nasopharyngeal carcinoma who receive radiation plus carbogen and nicotinamide, but further study is needed.
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Affiliation(s)
- Lu Xueguan
- Department of Radiation Oncology, Second Affiliated Hospital of Soochow University, Suzhou, China.
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Comparative pharmacokinetics, biodistribution, metabolism and hypoxia-dependent uptake of [18F]-EF3 and [18F]-MISO in rodent tumor models. Radiother Oncol 2008; 89:353-60. [PMID: 18649964 DOI: 10.1016/j.radonc.2008.06.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2008] [Revised: 05/30/2008] [Accepted: 06/18/2008] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND PURPOSE [18F]-EF3 allows non-invasive detection of hypoxia. In the framework of its validation, we aimed at comparing its pharmacokinetics, biodistribution, metabolism and specificity for hypoxia with the hypoxia tracer [18F]-FMISO. MATERIALS AND METHODS C3H mice were injected IV with 3.7-18.5 MBq of one of the two tracers. For pharmacokinetics experiments, blood, urines and feces were collected. For biodistribution experiments, 13 different organs were harvested. To assess the hypoxia-specificity of the tracers, intramuscular syngeneic FSA II tumor bearing mice breathing air or carbogen were used. Animals were sacrificed from 5 to 440 min after injection. Radioactivity was assessed ex-vivo in a gamma counter. Tracer metabolites were assessed with radio-HPLC of acetonitrile soluble fractions of tissues. RESULTS Elimination half-life in blood (mono-exponential fit) reached 81.8 and 99.7 min for [18F]-EF3 and [18F]-MISO, respectively (NS). After 440 min, 71+/-7% (mean+/-SD) of injected activity of [18F]-EF3 was collected in the urine while 9+/-2% was collected in the feces, compared to 71+/-15% and 23+/-15% for [18F]-MISO (NS). Biodistribution was similar with a homogeneous distribution in most organs as early as 5 min after injection. With time, an increased activity in organs involved in excretion (kidney, bladder, liver and GI tract) was measured for both tracers; however, an increased background activity in "oxic" normal tissues (brain, lung, and esophagus) was also observed for [18F]-MISO. The percentage of metabolites was higher for [18F]-MISO compared to [18F]-EF3 in nearly all samples. Tumor-to-muscle ratios (TMRs) ranging from 2 to 4 were obtained under air-breathing condition for both tracers. CONCLUSION Both tracers exhibited a similar pharmacokinetics and biodistribution in mice and accumulated in an hypoxia-dependent manner in tumors. However, more aspecific activity was observed with [18F]-MISO at late time points after tracer injection in normal tissues.
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Positron Emission Tomography Imaging of Tumor Hypoxia and Angiogenesis. Cancer Imaging 2008. [DOI: 10.1016/b978-012374212-4.50091-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Grosu AL, Souvatzoglou M, Röper B, Dobritz M, Wiedenmann N, Jacob V, Wester HJ, Reischl G, Machulla HJ, Schwaiger M, Molls M, Piert M. Hypoxia imaging with FAZA-PET and theoretical considerations with regard to dose painting for individualization of radiotherapy in patients with head and neck cancer. Int J Radiat Oncol Biol Phys 2007; 69:541-51. [PMID: 17869667 DOI: 10.1016/j.ijrobp.2007.05.079] [Citation(s) in RCA: 164] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2007] [Revised: 05/22/2007] [Accepted: 05/25/2007] [Indexed: 12/12/2022]
Abstract
PURPOSE To evaluate the role of hypoxia positron emission tomography (PET) using [18F]fluoroazomycin-arabinoside (FAZA) in head and neck cancer for radiation treatment planning using intensity-modulated radiotherapy and dose painting. METHODS AND MATERIALS Eighteen patients with advanced squamous cell head and neck cancer were included. Both FAZA-PET and axial CT were performed using mask fixation. The data were coregistered using software based on mutual information. Contours of tumor (primary gross tumor volume, GTV/CT-P) and lymph node metastases (GTV/CT-N) were outlined manually, and FAZA standardized uptake values (SUVs) were calculated automatically. The hypoxic subvolume (GTV/PET-FAZA) having at least 50% more FAZA uptake than background (mean SUV) neck muscle tissue was contoured automatically within GTV/CT-P (GTV/PET-FAZA-P) and GTV/CT-N (GTV/PET-FAZA-N). RESULTS The median GTV/PET-FAZA-P was 4.6 mL, representing 10.8% (range, 0.7-52%) of the GTV/CT-P. The GTV/PET-FAZA-P failed to correlate significantly with the GTV/CT-P (p = 0.06). The median GTV/PET-FAZA-N was 4.1 mL, representing 8.3% (range, 2.2-51.3%) of the GTV/CT-N. It was significantly correlated with the GTV/PET-N (p = 0.006). The GTV/PET-FAZA-P was located in a single confluent area in 11 of 18 patients (61%) and was diffusely dispersed in the whole GTV/CT-P in 4 of 18 patients (22%), whereas no hypoxic areas were identified in 3 of 18 patients (17%). The GTV/PET-FAZA-N was outlined as a single confluent region in 7 of 18 patients (39%), in multiple diffuse hypoxic regions in 4 of 18 patients (22%), and was not delineated in 7 of 18 patients (39%). CONCLUSION This study demonstrates that FAZA-PET imaging could be used for a hypoxia-directed intensity-modulated radiotherapy approach in head and neck cancer.
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Affiliation(s)
- Anca-Ligia Grosu
- Department of Radiation Oncology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
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Abstract
The purpose of this review is to provide an overview of the methods available for imaging tissue oxygenation. The following imaging methods are reviewed: phosphorescence, near-infrared (NIR), positron emission tomography (PET), magnetic resonance imaging ((19)F MRI and BOLD MRI), and electron paramagnetic resonance (EPR). The methods are based on different principles and differ in their ability to accurately quantify tissue oxygenation, either the absolute value of a particular measure of oxygenation (partial pressure of oxygen, concentration), or a parameter related to it (oxygen saturation). Methods that can provide images of relative changes in oxygenation or visualization of hypoxia in a specific tissue of interest are also considered valuable tools for biomedical research and clinical applications.
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Affiliation(s)
- Deepti S Vikram
- Center for Biomedical EPR Spectroscopy and Imaging, Comprehensive Cancer Center, Davis Heart and Lung Research Institute, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA
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Souvatzoglou M, Grosu AL, Röper B, Krause BJ, Beck R, Reischl G, Picchio M, Machulla HJ, Wester HJ, Piert M. Tumour hypoxia imaging with [18F]FAZA PET in head and neck cancer patients: a pilot study. Eur J Nucl Med Mol Imaging 2007; 34:1566-75. [PMID: 17447061 DOI: 10.1007/s00259-007-0424-3] [Citation(s) in RCA: 132] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2006] [Accepted: 02/22/2007] [Indexed: 12/12/2022]
Abstract
PURPOSE Hypoxia is an important negative prognostic factor for radiation treatment of head and neck cancer. This study was performed to evaluate the feasibility of use of (18)F-labelled fluoroazomycin arabinoside ([(18)F]FAZA) for clinical PET imaging of tumour hypoxia. METHODS Eleven patients (age 59.6 +/- 9 years) with untreated advanced head and neck cancer were included. After injection of approximately 300 MBq of [(18)F]FAZA, a dynamic sequence up to 60 min was acquired on an ECAT HR+ PET scanner. In addition, approximately 2 and 4 h p.i., static whole-body PET (n = 5) or PET/CT (n = 6) imaging was performed. PET data were reconstructed iteratively (OSEM) and fused with CT images (either an external CT or the CT of integrated PET/CT). Standardised uptake values (SUVs) and tumour-to-muscle (T/M) ratios were calculated in tumour and normal tissues. Also, the tumour volume displaying a T/M ratio >1.5 was determined. RESULTS Within the first 60 min of the dynamic sequence, the T/M ratio generally decreased, while generally increasing at later time points. At 2 h p.i., the tumour SUV(max) and SUV(mean) were found to be 2.3 +/- 0.5 (range 1.5-3.4) and 1.4 +/- 0.3 (range 1.0-2.1), respectively. The mean T/M ratio at 2 h p.i. was 2.0 +/- 0.3 (range 1.6-2.4). The tumour volume displaying a T/M ratio above 1.5 was highly variable. At 2 h p.i., [(18)F]FAZA organ distribution was determined as follows: kidney > gallbladder > liver > tumour > muscle > bone > brain > lung. CONCLUSION [(18)F]FAZA PET imaging appears feasible in head and neck cancer patients, and the achieved image quality is adequate for clinical purposes. Based on our initial results, [(18)F]FAZA warrants further evaluation as a hypoxia PET tracer for imaging of cancer.
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Affiliation(s)
- M Souvatzoglou
- Department of Nuclear Medicine, Technische Universität München, Ismaningerstr. 22, 81675 Munich, Germany
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Tanabe K, Zhang Z, Ito T, Hatta H, Nishimoto SI. Current molecular design of intelligent drugs and imaging probes targeting tumor-specific microenvironments. Org Biomol Chem 2007; 5:3745-57. [DOI: 10.1039/b711244k] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Abstract
The microenvironment of a tumour, in particular its hypoxic status, is a crucial factor in its response to radiotherapy. Conventional techniques for measuring hypoxia are either invasive or follow surgical intervention, and thus not ideal. Positron emission tomography allows the non-invasive pre-surgical assessment of oxygen status by measuring the spatiotemporal distribution of hypoxia-specific tracers. However, the relationship between levels of uptake and the underlying oxygen tension are yet to be elucidated. Furthermore, it is not fully understood how changes in the underlying physiology affect the appearance of uptake. This paper presents a modular simulation of the tumour microenvironment, underpinned by a probability density function (PDF) to model the vasculature. The model is solved numerically, to simulate both the steady-state oxygenation of a tumour and the spatiotemporal distribution of the hypoxia-specific tracer, [18F]-fluoromisonidazole (Fmiso), in a 2D environment. The results show that using a PDF to represent the vasculature effectively captures the 'hypoxic island' appearance of oxygen-deficient tissues seen ex vivo. Simulated tissue activity curves (TACs) demonstrate the general two-stage trend of empirical data, with an initial perfusion-dominated uptake, followed by hypoxia-specific binding. In well-perfused tissue, activity follows plasma levels in early stages, with binding of Fmiso only becoming apparent at a later stage. In structurally hypoxic tissue, a more gradual initial increase in activity is observed, followed by the same accumulation slope. We demonstrate the utility of theoretical modelling of tracer uptake, by quantifying the changes in TAC structure that arise as a result of altering key physiological characteristics. For example, by decreasing either the proximity of tissue to the vasculature, or the effective diffusion coefficient of Fmiso, we can observe a shift of TAC structure from corresponding to well-perfused to avascular regions, despite wholly different underlying causes.
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Affiliation(s)
- Catherine J Kelly
- Wolfson Medical Vision Laboratory, Information Engineering, University of Oxford, Parks Road, OX1 3PJ, UK.
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Zimny M, Gagel B, DiMartino E, Hamacher K, Coenen HH, Westhofen M, Eble M, Buell U, Reinartz P. FDG--a marker of tumour hypoxia? A comparison with [18F]fluoromisonidazole and pO2-polarography in metastatic head and neck cancer. Eur J Nucl Med Mol Imaging 2006; 33:1426-31. [PMID: 16841141 DOI: 10.1007/s00259-006-0175-6] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2006] [Accepted: 05/11/2006] [Indexed: 02/08/2023]
Abstract
PURPOSE Experimental data suggest that the accumulation of [(18)F]fluorodeoxyglucose (FDG) in malignant tumours is related to regional hypoxia. The aim of this study was to evaluate the clinical potential of FDG positron emission tomography (PET) to assess tumour hypoxia in comparison with [(18)F]fluoromisonidazole (FMISO) PET and pO(2)-polarography. METHODS Twenty-four patients with head and neck malignancies underwent FDG PET, FMISO PET, and pO(2)-polarography within 1 week. Parameters of pO(2)-polarography were the relative frequency of pO(2) readings <or=2.5 mmHg, <or=5 mmHg and <or=10 mmHg, respectively, as well as the mean and median pO(2). RESULTS We observed a moderate correlation of the maximum standardised uptake value (SUV) of FDG with the tumour to blood ratio of FMISO at 2 h (R=0.53, p<0.05). However, SUV of FDG was similar in hypoxic and normoxic tumours as defined by pO(2)-polarography (6.9+/-3.2 vs 6.2+/-3.0, NS), and the FDG uptake was not correlated with the results of pO(2)-polarography. The retention of FMISO was significantly higher in hypoxic tumours than in normoxic tumours (tumour to muscle ratio at 2 h: 1.8+/-0.4 vs 1.4+/-0.1, p<0.05), and the FMISO tumour to muscle ratio showed a strong correlation with the frequency of pO(2) readings <or=5 mmHg (R=0.80, p<0.001). CONCLUSION These results support the hypothesis that tumour hypoxia has an effect on glucose metabolism. However, other factors affecting FDG uptake may be more predominant in chronic hypoxia, and thus FDG PET cannot reliably differentiate hypoxic from normoxic tumours.
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Affiliation(s)
- Michael Zimny
- Department of Nuclear Medicine, University Hospital Aachen, Aachen, Germany.
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Rajendran JG, Hendrickson KRG, Spence AM, Muzi M, Krohn KA, Mankoff DA. Hypoxia imaging-directed radiation treatment planning. Eur J Nucl Med Mol Imaging 2006; 33 Suppl 1:44-53. [PMID: 16763816 DOI: 10.1007/s00259-006-0135-1] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Increasing evidence supports the role of the tumor microenvironment in modulating cancer behavior. Tissue hypoxia, an important and common condition affecting the tumor microenvironment, is well established as a resistance factor in radiotherapy. Increasing evidence points to the ability of hypoxia to induce the expression of gene products, which confer aggressive tumor behavior and promote broad resistance to therapy. These factors suggest that determining the presence or absence of tumor hypoxia is important in planning cancer therapy. Recent advances in PET hypoxia imaging, conformal radiotherapy, and imaging-directed radiotherapy treatment planning now make it possible to perform hypoxia-directed radiotherapy. We review the biological aspects of tumor hypoxia and PET imaging approaches for measuring tumor hypoxia, along with methods for conformal radiotherapy and image-guided treatment, all of which provide the underpinnings for hypoxia-directed therapy. As a case example, we review emerging data on PET imaging of hypoxia to direct radiotherapy.
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Affiliation(s)
- J G Rajendran
- Department of Radiology, University of Washington, Seattle, WA 98195, USA.
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Ito M, Yang DJ, Mawlawi O, Mendez R, Oh CS, Azhdarinia A, Greenwell AC, Yu DF, Kim EE. PET and planar imaging of tumor hypoxia with labeled metronidazole. Acad Radiol 2006; 13:598-609. [PMID: 16627201 DOI: 10.1016/j.acra.2006.01.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2005] [Revised: 01/08/2006] [Accepted: 01/09/2006] [Indexed: 10/24/2022]
Abstract
RATIONALE AND OBJECTIVES This study was aimed to develop 99mTc- and 68Ga-labeled metronidazole (MN) using ethylenedicysteine (EC) as a chelator and evaluate their potential use to assess tumor hypoxia. MATERIALS AND METHODS EC-MN was labeled with 99mTc in the presence of tin (II) chloride. Labeling EC-MN with 68Ga was achieved by adding 68GaCl3 (2 mCi with 3.4 microg cold GaCl3). In vitro cellular uptakes of 99mTc- and 68Ga-EC-MN were obtained in various types of tumor cells at 0.5-4 hours. Tissue distribution and PET imaging of 99mTc and 68Ga-EC-MN were evaluated in breast tumor-bearing rats at 0.5-4 hours. Tumor oxygen tension was measured using an oxygen probe. RESULTS There were similar cellular uptakes (2-10%) between 99mTc- and 68Ga-EC-MN at 0.5-4 hours. In vivo biodistribution of 99mTc- and 68Ga-EC-MN in breast tumor-bearing rats showed increased tumor-to-blood and tumor-to-muscle count density ratios as a function of time. Positron emission tomography images confirmed that the tumors could be visualized clearly with 68Ga-EC-MN. Oxygen tension in tumor tissue was determined to be 6-10 mm Hg compared with 40-50 mm Hg in normal muscle tissue. CONCLUSIONS The results indicated that it is feasible to use 99mTc- and 68Ga-EC-MN for assessment of tumor hypoxia. These agents may be useful in selecting and evaluating cancer therapy.
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Affiliation(s)
- Megumi Ito
- Division of Diagnostic Imaging, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
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Lawrentschuk N, Poon AMT, Foo SS, Putra LGJ, Murone C, Davis ID, Bolton DM, Scott AM. Assessing regional hypoxia in human renal tumours using 18F-fluoromisonidazole positron emission tomography. BJU Int 2005; 96:540-6. [PMID: 16104907 DOI: 10.1111/j.1464-410x.2005.05681.x] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To assess renal tumours for hypoxic regions using 18F-fluoromisonidazole (18F-FMISO) positron emission tomography (PET), a recognized noninvasive method for detecting hypoxia in tumours, as renal cell carcinoma (RCC) can be potentially cured with nephrectomy but recurrence develops in most patients, who then respond poorly to treatments such as chemotherapy, and hypoxia is known to confer resistance to radiotherapy and chemotherapy in many solid tumours. PATIENTS AND METHODS In all, 17 patients had 18F-FMISO PET scans before nephrectomy for presumed RCC. Specimens were examined histologically, and immunohistochemistry was used to compare the microvessel density (MVD) as an indicator of angiogenesis in the tumour and normal parenchyma, in 15 patients. Tumour oxygenation was measured invasively in three patients using a polarographic oxygen sensor probe. RESULTS Of the 15 patients with histological results, 11 had RCC and four had other tumours. Although there was a trend there was no statistically significant (P = 0.14) difference in the maximum standardized uptake value (SUV(max)) when comparing the region of the kidney involved with RCC; the mean (95% confidence interval) SUV(max) in the tumours was 1.3 (0.15), whilst that in the normal contralateral kidney was 1.1 (0.22). The MVD was greater in RCC, at 13.7 (3.1) mean vessels per high-power field than in normal tissue, at 6.9 (1.9). Hypoxia as measured polarographically was detected in three RCCs (median pO2 9.6 mmHg) compared to normal parenchyma at 37.6 mmHg. CONCLUSIONS Although 18F-FMISO scans showed significant uptake in other solid tumours, there was only mild 18F-FMISO uptake in the present RCCs. The invasive measurements indicated that there was hypoxia in RCC, but the median pO2 did not fall below 9.5 mmHg. Further direct studies of renal tumour oxygenation combined with therapies directed towards hypoxia may allow a better understanding of the relationship between 18F-FMISO results and the biological significance of hypoxia in RCC.
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Abstract
There is a clear need in cancer treatment for a noninvasive imaging assay that evaluates the oxygenation status and heterogeneity of hypoxia and angiogenesis in individual patients. Such an assay could be used to select alternative treatments and to monitor the effects of treatment. Of the several methods available, each imaging procedure has at least one disadvantage. The limited quantitative potential of single-photon emission CT and MR imaging always limits tracer imaging based on these detection systems. PET imaging with FMISO and Cu-ATSM is ready for coordinated multicenter trials, however, that should move aggressively forward to resolve the debate over the importance of hypoxia in limiting response to cancer therapy. Advances in radiation treatment planning, such as intensity-modulated radiotherapy, provide the ability to customize radiation delivery based on physical conformity. With incorporation of regional biologic information, such as hypoxia and proliferating vascular density in treatment planning, imaging can create a biologic profile of the tumor to direct radiation therapy. Presence of widespread hypoxia in the tumor benefits from a systemic hypoxic cell cytotoxin. Angiogenesis is also an important therapeutic target. Imaging hypoxia and angiogenesis complements the efforts in development of antiangiogenesis and hypoxia-targeted drugs. The complementary use of hypoxia and angiogenesis imaging methods should provide the impetus for development and clinical evaluation of novel drugs targeted at angiogenesis and hypoxia. Hypoxia imaging brings in information different from that of FDG-PET but it will play an important niche role in oncologic imaging in the near future. FMISO, radioiodinated azamycin arabinosides, and Cu-ATSM are all being evaluated in patients. The Cu-ATSM images show the best contrast early after injection but these images are confounded by blood flow and their mechanism of localization is one step removed from the intracellular O2 concentration. FMISO has been criticized as inadequate because of its clearance characteristics, but its uptake after 2 hours is probably the most purely reflective of regional PO2 at the time the radiopharmaceutical is used. The FMISO images show less contrast than those of Cu-ATSM because of the lipophilicity and slower clearance of FMISO but attempts to increase the rate of clearance led to tracers whose distribution is contaminated by blood flow effects. For single-photon emission CT the only option is radioiodinated azamycin arabinosides, because the technetium agents are not yet ready for clinical evaluation. Rather than develop new and improved hypoxia agents, or even quibbling about the pros and cons of alternative agents, the nuclear medicine community needs to convince the oncology community that imaging hypoxia is an important procedure that can lead to improved treatment outcome.
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Affiliation(s)
- Joseph G Rajendran
- Division of Nuclear Medicine, Department of Radiology, Box 356113, University of Washington, Seattle, WA 98195, USA.
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Falcao ALE, Reutens DC, Markus R, Koga M, Read SJ, Tochon-Danguy H, Sachinidis J, Howells DW, Donnan GA. The resistance to ischemia of white and gray matter after stroke. Ann Neurol 2005; 56:695-701. [PMID: 15505775 DOI: 10.1002/ana.20265] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
A contributing factor to the failure of trials of neuroprotectants in acute ischemic stroke may be the differing vulnerability to ischemia of white compared with gray matter. To address this issue, we determined to establish the existence of potentially viable tissue in white matter and its evolution to infarction or salvage in both gray and white matter compartments in patients with ischemic stroke. Twenty-seven patients (mean age, 73.4 years) at a median of 16.5 hours after symptom onset were studied using the hypoxic marker 18F-misonidazole with positron emission tomography (PET). Tissue was segmented using an magnetic resonance probabilistic map. Although there was a greater volume of initially "at-risk tissue" in gray matter (58.3 cm3, 29.9-93.0 cm3 than white matter (42.0 cm3, 15.8-74.0 cm3; p <0.001) at the time of PET imaging, a higher proportion of this was still potentially viable in white matter (41.4%, 4.6-74.5%) than in gray matter (23.6%, 3.2-61.1%; p <0.05). However, a similar proportion in each compartment spontaneously survived. These data provide evidence for the existence of potentially salvageable tissue in human white matter and is consistent with it having a similar or even greater resistance to ischemia than gray matter. For the latter possibility, alternative therapeutic strategies may be required for its salvage.
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Affiliation(s)
- Antonio L E Falcao
- National Stroke Research Institute, Heidelberg Heights, Melbourne, Australia
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Mahy P, De Bast M, Leveque PH, Gillart J, Labar D, Marchand J, Gregoire V. Preclinical validation of the hypoxia tracer 2-(2-nitroimidazol-1-yl)- N-(3,3,3-[(18)F]trifluoropropyl)acetamide, [(18)F]EF3. Eur J Nucl Med Mol Imaging 2004; 31:1263-72. [PMID: 15197503 DOI: 10.1007/s00259-004-1573-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2004] [Accepted: 04/13/2004] [Indexed: 10/26/2022]
Abstract
The 2-nitroimidazole derivative 2-(2-nitroimidazol-1-yl)- N-(3,3,3-trifluoropropyl)acetamide (EF3) is a marker which forms adducts into hypoxic cells. Radiosynthesis of [(18)F]EF3 was recently performed by our group. Our aim was to study the pharmacokinetics, biodistribution, metabolism and specificity for hypoxia of [(18)F]EF3. MCa-4, SCC VII, NFSA, FSA, FSA II or Sa-NH tumour-bearing C3H mice were injected intravenously with [(18)F]EF3 and allowed to breathe air, 10% O(2) or carbogen until sacrifice 5-770 min after injection. Radioactivity was measured ex vivo in various organs, including urine and faeces. Selected organs were additionally processed to measure tracer metabolites with high-performance liquid chromatography. The half-life in blood was 73.9 min. [(18)F]EF3 was eliminated mainly via the kidneys, with 75% of the injected activity found in the urine by 12 h 50 min. The biodistribution was fast and homogeneous except in the brain and the bone, where it was significantly lower, and in the liver and the kidney, where it was significantly higher. In most organs, the exceptions being the gastrointestinal and urinary tract, tissue-to-blood ratios were below or close to unity. In tumours, a relative accumulation of the tracer was observed with time, which, at 220 min after injection, depended on tumour strain and oxygenation conditions, i.e. 10% O(2) significantly increased the tumour-to-muscle ratio whereas carbogen decreased it. [(18)F]EF3 was rapidly metabolised in the kidney and the liver. [(18)F]EF3 is a promising tracer for detection of tumour hypoxia. A phase I study in head and neck cancer patients is in progress at our institution.
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Affiliation(s)
- P Mahy
- Department of Radiation Oncology and Radiobiology Unit, Université catholique de Louvain, St-Luc University Hospital, 10 Ave Hippocrate, 1200, Brussels, Belgium
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Grönroos T, Bentzen L, Marjamäki P, Murata R, Horsman MR, Keiding S, Eskola O, Haaparanta M, Minn H, Solin O. Comparison of the biodistribution of two hypoxia markers [18F]FETNIM and [18F]FMISO in an experimental mammary carcinoma. Eur J Nucl Med Mol Imaging 2004; 31:513-20. [PMID: 14722675 DOI: 10.1007/s00259-003-1404-x] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2003] [Accepted: 10/30/2003] [Indexed: 12/12/2022]
Abstract
The first aim of this study was to compare the hypoxia imaging ability of fluorine-18 fluoroerythronitroimidazole ([18F]FETNIM) with that of fluorine-18 fluoromisonimidazole ([18F]FMISO) in murine tumours of different sizes under two different oxygenation conditions. Secondly, we wanted to assess the biodistribution of the markers in normal tissues under similar conditions. Female CDF1 mice with a C3H mammary carcinoma grown on their backs were used. Tumours were size matched and animals breathed either normal air (21% O(2)) or carbogen gas (95% O(2) + 5% CO(2)). The gassing procedure was begun 5 min before the intravenous injection of either [18F]FETNIM or [18F]FMISO and continued until the mice were sacrificed at 120 min. Blood, tumour, muscle, heart, lung, liver, kidney and fat were removed, counted for radioactivity and weighed. The tumour and muscle were frozen and cut with a cryomicrotome into sections. The spatial distribution of radioactivity from the tissue sections was determined with digital autoradiography. Estimation of the necrotic fraction was made on sections from formalin-fixed tumours. Digital autoradiography showed that the whole tumour-to-muscle radioactivity uptake ratios were significantly higher in normal air-breathing mice than in carbogen-treated mice for both [18F]FETNIM (4.9+/-2.6 vs 1.8+/-0.5; P<0.01) and [18F]FMISO (4.4+/-1.0 vs 1.5+/-0.4; P<0.01). The carbogen treatment had only slight effects on the biodistribution of either marker in normal tissues. The necrotic fraction determined in tumours did not correlate with the tumour volume or with the tumour-to-muscle radioactivity uptake ratio. This study shows that the uptake of both [18F]FETNIM and [18F]FMISO correlates with the oxygenation status in tumours. In addition, our data show no significant difference in the intratumoral uptake between the two markers. However, significantly higher radioactivity uptake values were measured for [18F]FMISO than for [18F]FETNIM in normal tissues.
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Affiliation(s)
- Tove Grönroos
- Medicity Research Laboratory, Turku PET Centre, Tykistökatu 6 A, 20520 Turku, Finland.
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Affiliation(s)
- G J R Cook
- Department of Nuclear Medicine & PET, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK
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Bentzen L, Keiding S, Nordsmark M, Falborg L, Hansen SB, Keller J, Nielsen OS, Overgaard J. Tumour oxygenation assessed by 18F-fluoromisonidazole PET and polarographic needle electrodes in human soft tissue tumours. Radiother Oncol 2003; 67:339-44. [PMID: 12865184 DOI: 10.1016/s0167-8140(03)00081-1] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND PURPOSE The aim of the study was to identify hypoxia in human soft tissue sarcomas (STS) by PET scanning using the hypoxia marker [18F]-fluoromisonidazole ([18F]FMISO) and invasive oxygen sensitive probes (Eppendorf pO2 Histograph, Germany). MATERIALS AND METHODS Thirteen patients with tumours suspected to be STS were examined by [18F]FMISO PET scanning, and eleven of these patients completed a set of Eppendorf pO2 Histograph measurements following the scanning. RESULTS AND DISCUSSION By histopathological diagnosis, seven tumours were shown to be STS and six tumours were benign. Ratios between tumour and muscle radioactivity and time activity curves for tumours and muscle tissue were examined in defined regions of interest. Only two malignant tumours showed [18F]FMISO uptake in higher amounts than muscle tissue over time. Hypoxia was present in both benign and malignant tumours as measured by the oxygen electrode method. CONCLUSIONS [18F]FMISO PET in our setting seemed not to be feasible for the detection of tumour hypoxia in human soft tissue tumours. Neither did it reflect the extent of hypoxia as determined with the oxygen electrode measurements.
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Affiliation(s)
- Lise Bentzen
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Noerrebrogade 4, DK-8000 Aarhus C, Denmark
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Abstract
Low tissue oxygen concentration has been shown to be important in the response of human tumors to radiation therapy, chemotherapy and other treatment modalities. Hypoxia is also known to be a prognostic indicator, as hypoxic human tumors are more biologically aggressive and are more likely to recur locally and metastasize. Herein, we discuss and summarize the various methods under investigation to directly or indirectly measure tissue oxygen in vivo. Secondly, we consider the advantages and disadvantages of each of these techniques. These considerations are made in light of our specific hypotheses that hypoxia should be measured as a continuum, not a binary measurement and that moderate, not severe hypoxia is of great biological consequence.
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Affiliation(s)
- Sydney M Evans
- School of Medicine, Department of Radiation Oncology, 195 John Morgan Building, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Sorger D, Patt M, Kumar P, Wiebe LI, Barthel H, Seese A, Dannenberg C, Tannapfel A, Kluge R, Sabri O. [18F]Fluoroazomycinarabinofuranoside (18FAZA) and [18F]Fluoromisonidazole (18FMISO): a comparative study of their selective uptake in hypoxic cells and PET imaging in experimental rat tumors. Nucl Med Biol 2003; 30:317-26. [PMID: 12745023 DOI: 10.1016/s0969-8051(02)00442-0] [Citation(s) in RCA: 169] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The present study compares the uptake of [(18)F]Fluoroazomycinarabinofuranoside ((18)FAZA), a recently developed hypoxia tracer for PET imaging of tissue hypoxia, with an established tracer [(18)F]Fluoromisonidazole ((18)FMISO) both in vitro, using Walker 256 rat carcinosarcoma cells, and in vivo in experimental rat tumors eleven to twelve days after tumor cell implantation. In vitro studies indicated that hypoxia-selective uptake of both (18)FAZA and (18)FMISO in tumor cells, 20 and 100 minutes post-incubation was of the same magnitude (20 min: 1.24 +/- 0.4% ((18)FAZA); 1.19 +/- 0.7% ((18)FMISO); 100 min: 3.6 +/- 1.6% ((18)FAZA); 3.3 +/- 1.7% ((18)FMISO)). PET imaging reflected a similar radiotracer distribution in rat tumors for (18)FAZA and (18)FMISO one h after radiotracer injection. The concentration of (18)FAZA in the tumors as measured by PET, however, was lower in comparison to (18)FMISO (SUV(FAZA) = 0.61 +/- 0.2 vs. SUV(FMISO) = 0.92 +/- 0.3, p < 0.05) although the tumor to muscle ratios for (18)FAZA and (18)FMISO did not differ in the PET images that were obtained after one h (SUV(FAZA) = 2.5 +/- 0.5 vs. SUV(FMISO) = 2.9 +/- 0.7). A comparison of PET data three h post-injection (SUV(FAZA) = 3.0 +/- 0.5 vs. SUV(FMISO) = 4.6 +/- 1.8, p < 0.05) demonstrated a lower (18)FAZA uptake that indicates a lower sensitivity of (18)FAZA in comparison to (18)FMISO in detecting hypoxic regions at a longer time in this animal model. However, these data also show a faster elimination of (18)FAZA from blood, viscera and muscle tissue, via the renal system. This advantage of a faster reduction of unspecific binding, in light of similar or marginally lower tumor uptake, warrants further investigation of (18)FAZA as a marker of regional hypoxia in tumors.
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Affiliation(s)
- Dietlind Sorger
- Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany.
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