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Bian Q, Li B, Zhang L, Sun Y, Zhao Z, Ding Y, Yu H. Molecular pathogenesis, mechanism and therapy of Cav1 in prostate cancer. Discov Oncol 2023; 14:196. [PMID: 37910338 PMCID: PMC10620365 DOI: 10.1007/s12672-023-00813-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 10/25/2023] [Indexed: 11/03/2023] Open
Abstract
Prostate cancer is the second incidence of malignant tumors in men worldwide. Its incidence and mortality are increasing year by year. Enhanced expression of Cav1 in prostate cancer has been linked to both proliferation and metastasis of cancer cells, influencing disease progression. Dysregulation of the Cav1 gene shows a notable association with prostate cancer. Nevertheless, there is no systematic review to report about molecular signal mechanism of Cav1 and drug treatment in prostate cancer. This article reviews the structure, physiological and pathological functions of Cav1, the pathogenic signaling pathways involved in prostate cancer, and the current drug treatment of prostate cancer. Cav1 mainly affects the occurrence of prostate cancer through AKT/mTOR, H-RAS/PLCε, CD147/MMPs and other pathways, as well as substance metabolism including lipid metabolism and aerobic glycolysis. Baicalein, simvastatin, triptolide and other drugs can effectively inhibit the growth of prostate cancer. As a biomarker of prostate cancer, Cav1 may provide a potential therapeutic target for the treatment of prostate cancer.
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Affiliation(s)
- Qiang Bian
- Department of Pathophysiology, Weifang Medicine University, Weifang, 261053, Shandong, People's Republic of China
- Department of Biochemistry, Jining Medical University, Jining, 272067, Shandong, People's Republic of China
- The Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272100, Shandong, People's Republic of China
| | - Bei Li
- Department of Radiological Image, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, People's Republic of China
| | - Luting Zhang
- Department of Biochemistry, Jining Medical University, Jining, 272067, Shandong, People's Republic of China
| | - Yinuo Sun
- Department of Biochemistry, Jining Medical University, Jining, 272067, Shandong, People's Republic of China
| | - Zhankui Zhao
- The Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272100, Shandong, People's Republic of China
| | - Yi Ding
- Department of Pathophysiology, Weifang Medicine University, Weifang, 261053, Shandong, People's Republic of China.
| | - Honglian Yu
- Department of Biochemistry, Jining Medical University, Jining, 272067, Shandong, People's Republic of China.
- The Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272100, Shandong, People's Republic of China.
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Zhang Q, Li W. Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy. World J Stem Cells 2022; 14:267-286. [PMID: 35662861 PMCID: PMC9136564 DOI: 10.4252/wjsc.v14.i4.267] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/19/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.
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Affiliation(s)
- Qi Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Li
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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3
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Bailey JJ, Wuest M, Wagner M, Bhardwaj A, Wängler C, Wängler B, Valliant JF, Schirrmacher R, Wuest F. Synthesis and Preclinical Evaluation of [ 18F]SiFA-PSMA Inhibitors in a Prostate Cancer Model. J Med Chem 2021; 64:15671-15689. [PMID: 34672630 DOI: 10.1021/acs.jmedchem.1c00812] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA) with gallium-68 (68Ga) and fluorine-18 (18F) radiotracers has aroused tremendous interest over the past few years. The use of organosilicon-[18F]fluoride acceptors (SiFA) conjugated to urea-based peptidomimetic PSMA inhibitors provides a "kit-like" multidose synthesis technology. Nine novel 18F-labeled SiFA-bearing PSMA inhibitors with different linker moieties were synthesized and analyzed for their in vitro binding against [125I]I-TAAG-PSMA in LNCaP cells. IC50 values ranged from 58-570 nM. Among all compounds, [18F]SiFA-Asp2-PEG3-PSMA (IC50 = 125 nM) showed the highest tumor uptake in LNCaP tumors (SUV60min 0.73). A substantial increase in molar activity (Am) (from 7.5 ± 0.5 to 86 ± 3 GBq/μmol) led to a significant increase in LNCaP tumor uptake (SUV60min 1.18; Δ 0.45 corresponding to +62%). In vivo blocking with DCFPyL resulted in -32% uptake after 60 min. The SiFA-isotopic exchange chemistry offers a method that is readily adaptable for a "kit-type" labeling procedure and clinical translation.
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Affiliation(s)
- Justin J Bailey
- Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada
| | - Melinda Wuest
- Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada
| | - Michael Wagner
- Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada
| | - Atul Bhardwaj
- Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada
| | - Carmen Wängler
- Clinic of Radiology and Nuclear Medicine, Biomedical Chemistry and Clinic of Radiology and Nuclear Medicine, Molecular Imaging and Radiochemistry, Medical Faculty Mannheim of Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim 68167, Germany
| | - Bjoern Wängler
- Clinic of Radiology and Nuclear Medicine, Biomedical Chemistry and Clinic of Radiology and Nuclear Medicine, Molecular Imaging and Radiochemistry, Medical Faculty Mannheim of Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim 68167, Germany
| | - John F Valliant
- Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street, Hamilton, Ontario L8S 4K1, Canada
| | - Ralf Schirrmacher
- Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada
| | - Frank Wuest
- Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada
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Smallwood TB, Clark RJ. Advances in venom peptide drug discovery: where are we at and where are we heading? Expert Opin Drug Discov 2021; 16:1163-1173. [PMID: 33914674 DOI: 10.1080/17460441.2021.1922386] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Introduction: Animal venoms are a complex mixture of bioactive molecules that have evolved over millions of years for prey capture and defense from predators. Venom consists of many different types of molecules, with disulfide-rich peptides being a major component in most venoms. The study of these potent and highly selective molecules has led to the development of venom-derived drugs for diseases such as type 2 diabetes mellitus and chronic pain. As technologies have improved, more bioactive peptides have been discovered from venomous animals. Many of these molecules may have applications as tools for understanding normal and disease physiology, therapeutics, cosmetics or in agriculture.Areas covered: This article reviews venom-derived drugs approved by the FDA and venom-derived peptides currently in development. It discusses the challenges faced by venom-derived peptide drugs during drug development and the future for venom-derived peptides.Expert opinion: New techniques such as toxin driven discovery are expanding the pipeline of venom-derived peptides. There are many venom-derived peptides currently in preclinical and clinical trials that would have remained undiscovered using traditional approaches. A renewed focus on venoms, with advances in technology, will broaden the diversity of venom-derived peptide therapeutics and expand our knowledge of their molecular targets.
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Affiliation(s)
- Taylor B Smallwood
- Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, St. Lucia, Australia
| | - Richard J Clark
- Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, St. Lucia, Australia
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Chaudhari AJ, Badawi RD. Application-specific nuclear medical in vivoimaging devices. Phys Med Biol 2021; 66:10TR01. [PMID: 33770765 DOI: 10.1088/1361-6560/abf275] [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: 11/05/2019] [Accepted: 03/26/2021] [Indexed: 11/11/2022]
Abstract
Nuclear medical imaging devices, such as those enabling photon emission imaging (gamma camera, single photon emission computed tomography, or positron emission imaging), that are typically used in today's clinics are optimized for assessing large portions of the human body, and are classified as whole-body imaging systems. These systems have known limitations for organ imaging, therefore application-specific devices have been designed, constructed and evaluated. These devices, given their compact nature and superior technical characteristics, such as their higher detection sensitivity and spatial resolution for organ imaging compared to whole-body imaging systems, have shown promise for niche applications. Several of these devices have further been integrated with complementary anatomical imaging devices. The objectives of this review article are to (1) provide an overview of such application-specific nuclear imaging devices that were developed over the past two decades (in the twenty-first century), with emphasis on brain, cardiac, breast, and prostate imaging; and (2) discuss the rationale, advantages and challenges associated with the translation of these devices for routine clinical imaging. Finally, a perspective on the future prospects for application-specific devices is provided, which is that sustained effort is required both to overcome design limitations which impact their utility (where these exist) and to collect the data required to define their clinical value.
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Affiliation(s)
- Abhijit J Chaudhari
- Department of Radiology, University of California Davis, Sacramento, CA 95817, United States of America
- Center for Molecular and Genomic Imaging, University of California Davis, Davis, CA 95616, United States of America
| | - Ramsey D Badawi
- Department of Radiology, University of California Davis, Sacramento, CA 95817, United States of America
- Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, United States of America
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Li M, Jiang D, Barnhart TE, Cao T, Engle JW, Chen W, Cai W. Immuno-PET imaging of VEGFR-2 expression in prostate cancer with 89Zr-labeled ramucirumab. Am J Cancer Res 2019; 9:2037-2046. [PMID: 31598404 PMCID: PMC6780657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 08/06/2019] [Indexed: 06/10/2023] Open
Abstract
The detection and monitoring of prostate cancer (PrCa) malignancies using most of the conventional strategies is challenging. As an over-expressed biomarker of PrCa, the vascular endothelial growth factor receptor 2 (VEGFR-2) can be delineated by non-invasive imaging to address such issue. Herein, we report the positron emission tomography (PET) of VEGFR-2 expression in a PrCa mice models by composing a novel tracer, [89Zr]zirconium-labeled clinical VEGFR-2 antibody (Ramucirumab), i.e. 89Zr-Df-R. The VEGFR-2 expression levels among three different PrCa cell lines (PC-3, LNCAP and LAPC-4) were confirmed by flow cytometry. The immuno-PET imaging and bio-distribution (Bio-D) study were conducted in subcutaneous PrCa mice models via the 89Zr-Df-R. The regions of interest (ROI) data showed that the uptake of 89Zr-Df-R in the positive PC-3 (9.5±3 %ID/g) tumors are obviously higher than those ones in the negative LNCAP (6.0±1.7 %ID/g) or LAPC-4 (4.3±0.7 %ID/g) tumors at 120 hours post-injection, while the accumulation of 89Zr-Df-R in PC-3 tumors (4.3±1.2 %ID/g)) could be significantly reduced by the blockade of unlabeled Ramucirumab. These quantitative data coincide with the Bio-D data and proves the specificity. Additionally, the immuno-fluorescent staining results confirmed the expression pattern of VEGFR-2 among various PrCa tumors. Finally, the flow cytometry of PC-3 tumor tissue further proved that the binding of 89Zr-Df-R to VEGFR-2 primarily occurs on the PC-3 tumor cells. In summary, the description of the VEGFR-2 expression in PrCa by in-vivo PET with 89Zr-Df-R is feasible and it may shed light on the early detection of foci and dynamic monitoring of anti-VEGFR-2 therapy in PrCa.
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Affiliation(s)
- Miao Li
- Department of Radiology, The First Affiliated Hospital of Xi’an Jiaotong University277 West Yanta Road, Xi’an 710061, Shaanxi, People’s Republic of China
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison1111 Highland Avenue, Madison 53705, Wisconsin, United States
| | - Dawei Jiang
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison1111 Highland Avenue, Madison 53705, Wisconsin, United States
| | - Todd E Barnhart
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison1111 Highland Avenue, Madison 53705, Wisconsin, United States
| | - Tianye Cao
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison1111 Highland Avenue, Madison 53705, Wisconsin, United States
| | - Jonathan W Engle
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison1111 Highland Avenue, Madison 53705, Wisconsin, United States
| | - Weiyu Chen
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison1111 Highland Avenue, Madison 53705, Wisconsin, United States
| | - Weibo Cai
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison1111 Highland Avenue, Madison 53705, Wisconsin, United States
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Pei X, Zheng D, She S, Fang Z, Zhang S, Hu H, Xu K, Wang Y. Elevated Expression Levels of PC3-Secreted Microprotein (PSMP) in Prostate Cancer Associated With Increased Xenograft Growth and Modification of Immune-Related Microenvironment. Front Oncol 2019; 9:724. [PMID: 31555577 PMCID: PMC6723336 DOI: 10.3389/fonc.2019.00724] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 07/22/2019] [Indexed: 12/19/2022] Open
Abstract
Prostate cancer (PCa), especially metastatic PCa, is one of the main cancer types accounting for male mortality worldwide. Over decades, researchers have tried to search for effective curative methods for PCa, but many attempts have failed. The therapeutic failure of PCa is usually due to off-target or side effects; thus, finding a key molecule that could prevent PCa metastatic progression has become the most important goal for curing aggressive PCa. In this study, we collected hundreds of PCa tissues and serum and urine samples from patients to verify the upregulated expression of PC3-secreted microprotein (PSMP) in PCa tumor tissues with high Gleason scores. According to biopsy results, PSMP expression was found related to extraprostatic extension (EPE), contributing to PCa metastasis. Mechanistically, recombinant PSMP protein could promote the proliferation both in vitro and in vivo, and rhPSMP could promote epithelial–mesenchymal transition (EMT) of PC3 in vitro. Additionally, PSMP could also influence cytokine production in the xenograft model and monocyte migration and macrophage polarization in vitro. Our most important finding was that neutralizing antibodies against PSMP could suppress xenograft PC3 growth and promote the survival of PC3 metastatic mice model, providing an effective option to cure human PCa.
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Affiliation(s)
- Xiaolei Pei
- Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China
| | - Danfeng Zheng
- Department of Laboratory Medicine, Center of Clinical Laboratory, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Shaoping She
- Key Laboratory of Medical Immunology, Ministry of Health, Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Zhiwei Fang
- Department of Urology, Peking University People's Hospital, Beijing, China
| | - Shiying Zhang
- Department of Urology, Peking University People's Hospital, Beijing, China
| | - Hao Hu
- Department of Urology, Peking University People's Hospital, Beijing, China
| | - Kexin Xu
- Department of Urology, Peking University People's Hospital, Beijing, China
| | - Ying Wang
- Key Laboratory of Medical Immunology, Ministry of Health, Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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Multifocal Meningiomas Mimicking Dural-Based Intracranial Metastases at 18F-Fluciclovine PET/CT. Clin Nucl Med 2019; 44:594-595. [DOI: 10.1097/rlu.0000000000002629] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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9
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Evaluation of new 99mTc-labeled HYNIC-bombesin analogue for prostate cancer imaging. J Radioanal Nucl Chem 2018. [DOI: 10.1007/s10967-018-5819-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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10
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Hamid AA, Kaushal T, Ashraf R, Singh A, Chand Gupta A, Prakash O, Sarkar J, Chanda D, Bawankule DU, Khan F, Shanker K, Aiyelaagbe OO, Negi AS. (22β,25R)-3β-Hydroxy-spirost-5-en-7-iminoxy-heptanoic acid exhibits anti-prostate cancer activity through caspase pathway. Steroids 2017; 119:43-52. [PMID: 28143704 DOI: 10.1016/j.steroids.2017.01.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 12/16/2016] [Accepted: 01/12/2017] [Indexed: 11/20/2022]
Abstract
Prostate cancer is one of the most common cancers in men. Diosgenin and related compounds are potential cytotoxic agents. Twelve diverse analogues of long chain fatty acid/ester of diosgenin-7-ketoxime have been prepared. Six of the analogues exhibited significant anticancer activity against a panel of human cancer cell lines with IC50 ranging from 12 to 35μM. Compound 16, the best representative of the series exerted S phase arrest in DU145 prostate cancer cells and induced apoptosis through caspase pathway. Additionally, these analogues inhibited lipopolysaccharide induced pro-inflammatory cytokines (TNF-α and IL-6) up to 47.7% and 23.3% respectively. Compound 16 was found to be safe in acute oral toxicity in Swiss albino mice up to 300mg/kg dose. The anticancer and antiinflammatory properties of compound 16 are important and can further be optimized for a better anti-prostate cancer candidate.
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Affiliation(s)
- A A Hamid
- CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India; Department of Chemistry, University of Ilorin, Ilorin, Nigeria
| | - Tanu Kaushal
- CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India
| | - Raghib Ashraf
- CSIR-Central Drug Research Institute (CSIR-CDRI), B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
| | - Arjun Singh
- CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India
| | - Amit Chand Gupta
- CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India
| | - Om Prakash
- CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India
| | - Jayanta Sarkar
- CSIR-Central Drug Research Institute (CSIR-CDRI), B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
| | - Debabrata Chanda
- CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India
| | - D U Bawankule
- CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India
| | - Feroz Khan
- CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India
| | - Karuna Shanker
- CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India
| | - O O Aiyelaagbe
- Organic Chemistry Unit, Department of Chemistry, University of Ibadan, Ibadan, Nigeria
| | - Arvind S Negi
- CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India.
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Jia X, Li Y, Sharma A, Li Y, Xie G, Wang G, Jiang J, Cheng Y, Ding X. Application of sequential factorial design and orthogonal array composite design (OACD) to study combination of 5 prostate cancer drugs. Comput Biol Chem 2017; 67:234-243. [PMID: 28189106 DOI: 10.1016/j.compbiolchem.2017.01.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 01/12/2017] [Accepted: 01/23/2017] [Indexed: 10/20/2022]
Abstract
Prostate cancer is one of the most common cancers among men in the United States. It is also a major leading cause of cancer death among men of all races. In order to treat prostate cancer, drug combinations are often applied. Drug combinations target at different pathways of cells can potentially lead to higher efficacy and lower toxicity due to drug synergy. In this paper, we sequentially applied a two-level design and a follow-up orthogonal array composite design (OACD) to investigate combinations of five anti-cancer drugs, namely, doxorubicin, docetaxel, paclitaxel, cis-dichlorodiamine platinum and dihydroartemisinin. Our initial screening using a two-level full factorial design identified doxorubicin and docetaxel as the most significant drugs. A follow-up experiment with an OACD revealed more complicated drug interactions among these 5 anti-cancer drugs. Quadratic effects of doxorubicin and paclitaxel appeared to be significant. A further investigation on contour plots of all the two-drug pairs indicated that combination of doxorubicin and docetaxel are the most effective companion, while the combination of cis-dichlorodiamine platinum and dihydroartemisinin showed unknown antagonistic effects which diminished the individual drug anti-cancer efficacy. These observations have significant practical implications in the understanding of anti-cancer drug mechanism that can facilitate clinical practice of better drug combinations.
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Affiliation(s)
- Xiaolong Jia
- Department of Urology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, Ningbo, Zhejiang 315010, China; School of Biomedical Engineering, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Yiyang Li
- School of Biomedical Engineering, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Alok Sharma
- School of Biomedical Engineering, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Yulong Li
- School of Biomedical Engineering, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Guohai Xie
- Department of Urology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, Ningbo, Zhejiang 315010, China
| | - Guoyao Wang
- Department of Urology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, Ningbo, Zhejiang 315010, China
| | - Junhui Jiang
- Department of Urology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, Ningbo, Zhejiang 315010, China
| | - Yue Cheng
- Department of Urology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, Ningbo, Zhejiang 315010, China.
| | - Xianting Ding
- School of Biomedical Engineering, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
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12
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Change in Salvage Radiotherapy Management Based on Guidance With FACBC (Fluciclovine) PET/CT in Postprostatectomy Recurrent Prostate Cancer. Clin Nucl Med 2017; 42:e22-e28. [PMID: 27749412 DOI: 10.1097/rlu.0000000000001379] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE We explored the influence of FACBC (fluciclovine) PET/CT on the decision to offer radiotherapy and radiotherapy treatment field recommendations in postprostatectomy patients with recurrent prostate cancer. PATIENTS AND METHODS After obtaining institutional review board approval and informed consent, 87 patients with detectable prostate-specific antigen (PSA) levels were recruited into a prospective clinical trial. After an initial provider-determined radiotherapy plan based on conventional imaging, 44 of 87 patients were randomized to additionally undergo fluciclovine PET/CT. Pre- and post-fluciclovine radiotherapy decisions were compared and changes were noted. Statistical significance of these decision changes was determined. RESULTS Two of 44 patients in the experimental arm dropped out before fluciclovine scanning. Thirty-four (81.0%) of 42 had positive results on fluciclovine. Overall radiotherapy decision was changed in 17 (40.5%) of 42. Mean PSA, original Gleason score, and prostatectomy-PET interval did not differ significantly between patients with and without radiotherapy decision changes. Two (4.8%) of 42 had the decision for radiotherapy withdrawn due to positive extrapelvic findings. Radiotherapy field decision was changed in 15 (35.7%) of 42. Eleven (73.3%) of 15 had fields changed from prostate bed only to both prostate bed and pelvis, while 4 (26.7%) of 15 had fields changed from both prostate bed and pelvis to prostate bed only. Changes in overall radiotherapy decision and field were statistically significant (P < 0.0001). However, the change in the decision to offer radiotherapy or not was not statistically significant (P = 0.15). CONCLUSIONS Fluciclovine PET/CT significantly changed radiotherapy management decisions in postprostatectomy patients with recurrent prostate cancer. Further work in determining differences in PSA-free survival is ongoing.
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Tang T, Yang Z, Zhang D, Qu J, Liu G, Zhang S. Clinicopathological study of 9 cases of prostate cancer involving the rectal wall. Diagn Pathol 2017; 12:8. [PMID: 28095874 PMCID: PMC5240329 DOI: 10.1186/s13000-017-0599-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 01/09/2017] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Prostate cancer involving the rectal wall is rare and may lead to diagnostic pitfalls. CASE PRESENTATION Out of 9504 patients with rectal tumors between January 2003 and January 2015, 9 patients (elderly with a mean age of 74 years) with prostate cancer involving the rectal wall were clinically misdiagnosed with rectal cancer. The lesions were located in the rectum, and included 3 circumferential rectal masses, 1 ulceration lesion, 1 crater-like mass, and 4 protruding lesions. Specimens were acquired using biopsy, fine needle aspiration, or resection. The initial symptoms of these patients included rectal urgency, bowel obstruction, and lower gastrointestinal bleeding. Prostate-related symptoms were not obvious. Histologically, 2 cases showed cancer cell invasion in the mucosa, 1 showed transmural invasion from the mucosa to subserosal soft tissues, and 7 cases had submucosa and muscularis propria involvement. All the 9 cases had muscularis propria involvement. However, there were no intraepithelial neoplasias in the mucosal layer, which is reminiscent of rectal carcinoma. The tumors consisted of small-sized or foamy cells that formed acinus-like, duct-like, and cribriform-like structures. We conducted histological staining and an immunohistochemical analysis for CDX-2, prostate-specific antigen (PSA), P504s, villin, carcinoembryonic antigen, CK-pan, cytokeratin 20, and Ki-67. All tumors were PSA and CK-pan positive, 5 of 9 tumors were P504s-positive, and all tumors were negative for the other markers. All patients underwent standard therapy for prostate cancer after the definitive pathological diagnosis. As of March 31, 2015, 8 patients were alive and 1 had died of prostate cancer 6 months posttreatment. CONCLUSIONS Adenocarcinoma appearing in the rectal wall is not always rectal carcinoma. It is necessary to perform a differential diagnosis for prostate cancer in cases of rectal malignant tumors in elderly male patients. Any treatment should be postponed until the final definitive diagnosis is reached.
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Affiliation(s)
- Tao Tang
- Department of Pathology, Tianjin Union Medical Center, Jieyuan Road, Hongqiao District, Tianjin, 300121 People’s Republic of China
| | - Zhengduo Yang
- Department of Pathology, Tianjin Union Medical Center, Jieyuan Road, Hongqiao District, Tianjin, 300121 People’s Republic of China
| | - Dan Zhang
- Department of Pathology, Tianjin Union Medical Center, Jieyuan Road, Hongqiao District, Tianjin, 300121 People’s Republic of China
| | - Jie Qu
- Department of Pathology, Tianjin Union Medical Center, Jieyuan Road, Hongqiao District, Tianjin, 300121 People’s Republic of China
| | - Guang Liu
- Department of Pathology, Tianjin Union Medical Center, Jieyuan Road, Hongqiao District, Tianjin, 300121 People’s Republic of China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Jieyuan Road, Hongqiao District, Tianjin, 300121 People’s Republic of China
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14
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Meller S, Meyer HA, Bethan B, Dietrich D, Maldonado SG, Lein M, Montani M, Reszka R, Schatz P, Peter E, Stephan C, Jung K, Kamlage B, Kristiansen G. Integration of tissue metabolomics, transcriptomics and immunohistochemistry reveals ERG- and gleason score-specific metabolomic alterations in prostate cancer. Oncotarget 2016; 7:1421-38. [PMID: 26623558 PMCID: PMC4811470 DOI: 10.18632/oncotarget.6370] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 11/15/2015] [Indexed: 01/05/2023] Open
Abstract
Integrated analysis of metabolomics, transcriptomics and immunohistochemistry can contribute to a deeper understanding of biological processes altered in cancer and possibly enable improved diagnostic or prognostic tests. In this study, a set of 254 metabolites was determined by gas-chromatography/liquid chromatography-mass spectrometry in matched malignant and non-malignant prostatectomy samples of 106 prostate cancer (PCa) patients. Transcription analysis of matched samples was performed on a set of 15 PCa patients using Affymetrix U133 Plus 2.0 arrays. Expression of several proteins was immunohistochemically determined in 41 matched patient samples and the association with clinico-pathological parameters was analyzed by an integrated data analysis. These results further outline the highly deregulated metabolism of fatty acids, sphingolipids and polyamines in PCa. For the first time, the impact of the ERG translocation on the metabolome was demonstrated, highlighting an altered fatty acid oxidation in TMPRSS2-ERG translocation positive PCa specimens. Furthermore, alterations in cholesterol metabolism were found preferentially in high grade tumors, enabling the cells to create energy storage. With this integrated analysis we could not only confirm several findings from previous metabolomic studies, but also contradict others and finally expand our concepts of deregulated biological pathways in PCa.
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Affiliation(s)
- Sebastian Meller
- Institute of Pathology, University Hospital of Bonn, Bonn, Germany
| | - Hellmuth-A Meyer
- Campus Wilhelminenhof, University of Applied Sciences, Berlin, Germany
| | | | - Dimo Dietrich
- Institute of Pathology, University Hospital of Bonn, Bonn, Germany
| | | | - Michael Lein
- Berlin Institute for Urologic Research, Berlin, Germany.,Department of Urology, University Teaching Hospital, Offenbach, Germany
| | - Matteo Montani
- Institute of Pathology, University of Bern, Bern, Switzerland
| | | | | | | | - Carsten Stephan
- Berlin Institute for Urologic Research, Berlin, Germany.,Department of Urology, University Hospital Charité, Berlin, Germany
| | - Klaus Jung
- Berlin Institute for Urologic Research, Berlin, Germany.,Department of Urology, University Hospital Charité, Berlin, Germany
| | | | - Glen Kristiansen
- Institute of Pathology, University Hospital of Bonn, Bonn, Germany
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15
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Yuan S, Wang L, Chen X, Fan B, Yuan Q, Zhang H, Yang D, Wang S. Triptolide inhibits the migration and invasion of human prostate cancer cells via Caveolin-1/CD147/MMPs pathway. Biomed Pharmacother 2016; 84:1776-1782. [DOI: 10.1016/j.biopha.2016.10.104] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 10/25/2016] [Accepted: 10/30/2016] [Indexed: 12/15/2022] Open
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16
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Arimoto MK, Higashi T, Nishii R, Kagawa S, Takahashi M, Kishibe Y, Yamauchi H, Ishitoya S, Oonishi H, Nakamoto Y, Togashi K. (11)C-methylaminoisobutyric acid (MeAIB) PET for evaluation of prostate cancer: compared with (18)F-fluorodeoxyglucose PET. Ann Nucl Med 2016; 30:553-62. [PMID: 27329084 DOI: 10.1007/s12149-016-1098-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 06/03/2016] [Indexed: 11/27/2022]
Abstract
OBJECTIVE α-N-methyl-(11)C-methylaminoisobutyric acid ((11)C-MeAIB) is a selective substrate of system A amino acid transport, and known to accumulate in malignant lesions. The aim of this study was to evaluate the utility of MeAIB PET for the assessment of prostate cancer, compared with FDG PET. METHODS Thirty-four men (age range 57-77 years) with prostate cancer were prospectively enrolled, and underwent MeAIB PET and FDG PET between January 2011 and January 2013. MeAIB PET and FDG PET were performed at 20 and 50 min post-injection, respectively. SUVmax of the prostate was calculated, and visual analysis was conducted for MeAIB and FDG PET studies. MRI images were visually evaluated if available. All patients received total prostatectomy subsequently, and imaging findings were compared with pathological results, including T stage, Gleason score, and tumor size. The patient-based and lesion-based sensitivity and specificity were calculated according to pathological significant cancer. RESULTS Mean value of SUVmax of (11)C-MeAIB PET and (18)F-FDG PET in prostate cancer were 3.18 (±1.90, range; 1.55-9.57) and 3.88 (±2.85, range; 2.04-14.47). MeAIB PET and FDG PET were positive by visual analysis in 47.1 % (16/34) and 44.1 % (15/34) of the patients. MRI was positive in 51.5 % (17/33). Pathological stage and Gleason score were as follows: Stage 2 (n = 23), 3 (n = 8), and 4 (n = 3); Gleason score 6 (n = 13), 7 (n = 16), 8 (n = 3), and 9 (n = 2). The sensitivities tended to be higher according to higher pathological T stage or Gleason sum score for both MeAIB and FDG PET studies. Visual analysis of both MeAIB PET and FDG PET had significant correlation with extraprostatic extension (p < 0.05). MeAIB PET and FDG PET had complementary results by visual analysis in the assessment of prostate cancer. The patient-based sensitivity of MeAIB PET, FDG PET, and MRI were 51.6, 48.4, and 56.7 %, respectively. The patient-based specificity of these modalities was 100 % for each modality. CONCLUSIONS MeAIB PET has better diagnostic results than FDG PET for the assessment of significant prostate cancer, and these PET studies showed complementary results. MRI has even better diagnostic results than (11)C-MeAIB PET. MeAIB accumulates in prostate cancer, which indicates that the system A amino acid transport pathway is activated in prostate cancer.
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Affiliation(s)
- Maya K Arimoto
- Shiga Medical Center Research Institute, 5-4-30 Moriyama, Moriyama, Shiga, 524-8524, Japan
- Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University, Graduate School of Medicine, 54, Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Kyoto, 606-8507, Japan
| | - Tatsuya Higashi
- Shiga Medical Center Research Institute, 5-4-30 Moriyama, Moriyama, Shiga, 524-8524, Japan.
| | - Ryuichi Nishii
- National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba, 263-8555, Japan
- Department of Radiology, Faculty of Medicine, Miyazaki University, 5200 Kihara, Kiyotake-cho, Miyazaki, Miyazaki, 889-1692, Japan
| | - Shinya Kagawa
- Shiga Medical Center Research Institute, 5-4-30 Moriyama, Moriyama, Shiga, 524-8524, Japan
| | - Masaaki Takahashi
- Shiga Medical Center Research Institute, 5-4-30 Moriyama, Moriyama, Shiga, 524-8524, Japan
| | - Yoshihiko Kishibe
- Shiga Medical Center Research Institute, 5-4-30 Moriyama, Moriyama, Shiga, 524-8524, Japan
| | - Hiroshi Yamauchi
- Shiga Medical Center Research Institute, 5-4-30 Moriyama, Moriyama, Shiga, 524-8524, Japan
| | - Satoshi Ishitoya
- Department of Urology, Shiga Medical Center, 5-4-30 Moriyama, Moriyama, Shiga, 524-8524, Japan
- Department of Urology, Otsu Red Cross Hospital, 1-1-35 Nagara, Otsu, Shiga, 520-0046, Japan
| | - Hiroyuki Oonishi
- Department of Urology, Shiga Medical Center, 5-4-30 Moriyama, Moriyama, Shiga, 524-8524, Japan
| | - Yuji Nakamoto
- Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University, Graduate School of Medicine, 54, Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Kyoto, 606-8507, Japan
| | - Kaori Togashi
- Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University, Graduate School of Medicine, 54, Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Kyoto, 606-8507, Japan
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17
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Bouvet V, Wuest M, Jans HS, Janzen N, Genady AR, Valliant JF, Benard F, Wuest F. Automated synthesis of [(18)F]DCFPyL via direct radiofluorination and validation in preclinical prostate cancer models. EJNMMI Res 2016; 6:40. [PMID: 27142881 PMCID: PMC4854855 DOI: 10.1186/s13550-016-0195-6] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 04/26/2016] [Indexed: 11/18/2022] Open
Abstract
Background Prostate-specific membrane antigen (PSMA) is frequently overexpressed and upregulated in prostate cancer. To date, various 18F- and 68Ga-labeled urea-based radiotracers for PET imaging of PSMA have been developed and entered clinical trials. Here, we describe an automated synthesis of [18F]DCFPyL via direct radiofluorination and validation in preclinical models of prostate cancer. Methods [18F]DCFPyL was synthesized via direct nucleophilic heteroaromatic substitution reaction in a single reactor TRACERlab FXFN automated synthesis unit. Radiopharmacological evaluation of [18F]DCFPyL involved internalization experiments, dynamic PET imaging in LNCaP (PSMA+) and PC3 (PSMA−) tumor-bearing BALB/c nude mice, biodistribution studies, and metabolic profiling. In addition, reversible two-tissue compartmental model analysis was used to quantify pharmacokinetics of [18F]DCFPyL in LNCaP and PC3 tumor models. Results Automated radiosynthesis afforded radiotracer [18F]DCFPyL in decay-corrected radiochemical yields of 23 ± 5 % (n = 10) within 55 min, including HPLC purification. Dynamic PET analysis revealed rapid and high uptake of radioactivity (SUV5min 0.95) in LNCaP tumors which increased over time (SUV60min 1.1). Radioactivity uptake in LNCaP tumors was blocked in the presence of nonradioactive DCFPyL (SUV60min 0.22). The muscle as reference tissue showed rapid and continuous clearance over time (SUV60min 0.06). Fast blood clearance of radioactivity resulted in tumor-blood ratios of 1.0 after 10 min and 8.3 after 60 min. PC3 tumors also showed continuous clearance of radioactivity over time (SUV60min 0.11). Kinetic analysis of PET data revealed the two-tissue compartmental model as best fit with K1 = 0.12, k2 = 0.18, k3 = 0.08, and k4 = 0.004 min−1, confirming molecular trapping of [18F]DCFPyL in PSMA+ LNCaP cells. Conclusions [18F]DCFPyL can be prepared for clinical applications simply and in good radiochemical yields via a direct radiofluorination synthesis route in a single reactor automated synthesis unit. Radiopharmacological evaluation of [18F]DCFPyL confirmed high PSMA-mediated tumor uptake combined with superior clearance parameters. Compartmental model analysis points to a two-step molecular trapping mechanism based on PSMA binding and subsequent internalization leading to retention of radioactivity in PSMA+ LNCaP tumors. Electronic supplementary material The online version of this article (doi:10.1186/s13550-016-0195-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Vincent Bouvet
- Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada
| | - Melinda Wuest
- Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada
| | - Hans-Soenke Jans
- Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada
| | - Nancy Janzen
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Canada
| | - Afaf R Genady
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Canada
| | - John F Valliant
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Canada
| | - Francois Benard
- Department of Radiology, University of British Columbia, Vancouver, Canada
| | - Frank Wuest
- Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada.
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18
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Schreibmann E, Schuster DM, Rossi PJ, Shelton J, Cooper S, Jani AB. Image Guided Planning for Prostate Carcinomas With Incorporation of Anti-3-[18F]FACBC (Fluciclovine) Positron Emission Tomography: Workflow and Initial Findings From a Randomized Trial. Int J Radiat Oncol Biol Phys 2016; 96:206-13. [PMID: 27511856 DOI: 10.1016/j.ijrobp.2016.04.023] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 04/08/2016] [Accepted: 04/17/2016] [Indexed: 01/14/2023]
Abstract
PURPOSE (18)F-Fluciclovine (anti-1-amino-3-[(18)F]fluorocyclobutane-1-carboxylic acid) is a novel positron emission tomography (PET)/computed tomography (CT) radiotracer that has demonstrated utility for detection of prostate cancer. Our goal is to report the initial results from a randomized controlled trial of the integration of (18)F-fluciclovine PET-CT into treatment planning for defining prostate bed and lymph node target volumes. METHODS AND MATERIALS We report our initial findings from a cohort of 41 patients, of the first enrolled on a randomized controlled trial, who were randomized to the (18)F-fluciclovine arm. All patients underwent (18)F-fluciclovine PET-CT for the detection of metabolic abnormalities and high-resolution CT for treatment planning. The 2 datasets were registered first by use of a rigid registration. If soft tissue displacement was observable, the rigid registration was improved with a deformable registration. Each (18)F-fluciclovine abnormality was segmented as a percentage of the maximum standard uptake value (SUV) within a small region of interest around the lesion. The percentage best describing the SUV falloff was integrated in planning by expanding standard target volumes with the PET abnormality. RESULTS In 21 of 55 abnormalities, a deformable registration was needed to map the (18)F-fluciclovine activity into the simulation CT. The most selected percentage was 50% of maximum SUV, although values ranging from 15% to 70% were used for specific patients, illustrating the need for a per-patient selection of a threshold SUV value. The inclusion of (18)F-fluciclovine changed the planning volumes for 46 abnormalities (83%) of the total 55, with 28 (51%) located in the lymph nodes, 11 (20%) in the prostate bed, 10 (18%) in the prostate, and 6 (11%) in the seminal vesicles. Only 9 PET abnormalities were fully contained in the standard target volumes based on the CT-based segmentations and did not necessitate expansion. CONCLUSIONS The use of (18)F-fluciclovine in postprostatectomy radiation therapy planning was feasible and led to augmentation of the target volumes in the majority (30 of 41) of the patients studied.
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Affiliation(s)
- Eduard Schreibmann
- Department of Radiation Oncology and Winship Cancer Institute of Emory University, Emory University, Atlanta, Georgia.
| | - David M Schuster
- Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia
| | - Peter J Rossi
- Department of Radiation Oncology and Winship Cancer Institute of Emory University, Emory University, Atlanta, Georgia
| | - Joseph Shelton
- Department of Radiation Oncology and Winship Cancer Institute of Emory University, Emory University, Atlanta, Georgia
| | - Sherrie Cooper
- Department of Radiation Oncology and Winship Cancer Institute of Emory University, Emory University, Atlanta, Georgia
| | - Ashesh B Jani
- Department of Radiation Oncology and Winship Cancer Institute of Emory University, Emory University, Atlanta, Georgia
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19
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Xu YP, Yang M. Advancement in treatment and diagnosis of pancreatic cancer with radiopharmaceuticals. World J Gastrointest Oncol 2016; 8:165-172. [PMID: 26909131 PMCID: PMC4753167 DOI: 10.4251/wjgo.v8.i2.165] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 09/30/2015] [Accepted: 12/18/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer (PC) is a major health problem. Conventional imaging modalities show limited accuracy for reliable assessment of the tumor. Recent researches suggest that molecular imaging techniques with tracers provide more biologically relevant information and are benefit for the diagnosis of the cancer. In addition, radiopharmaceuticals also play more important roles in treatment of the disease. This review summaries the advancement of the radiolabeled compounds in the theranostics of PC.
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20
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Harnessing the knowledge of animal toxins to generate drugs. Pharmacol Res 2016; 112:30-36. [PMID: 26826284 DOI: 10.1016/j.phrs.2016.01.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 01/07/2016] [Accepted: 01/12/2016] [Indexed: 11/20/2022]
Abstract
Animal toxins present high selectivity and specificity for their molecular targets, and have long been considered as prototypes for developing novel drugs, with some successful cases. In this regard, the variety of molecules found in animal venoms, which can be capable of affecting vital physiological systems, have providing the development of studies focusing on turning those molecules (toxins) into therapeutics to treat several diseases, such as chronic pain, hypertension, thrombosis, cancer, and so on. However, some important issues have been responsible for disrupting the toxin-based drug discovery projects. In this review, we have briefly highlighted the development of drugs based on animal toxins, discussing some successful cases as well as the main causes of failure, pointing out the recent strategies applied to overcome the difficulties related to the translational process in this kind of development scenario.
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21
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Zhu C, Xu Q, Pan D, Xu Y, Liu P, Yang R, Wang L, Sun X, Luo S, Yang M. Prostate cancer imaging of FSHR antagonist modified with a hydrophilic linker. CONTRAST MEDIA & MOLECULAR IMAGING 2015; 11:99-105. [DOI: 10.1002/cmmi.1662] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Revised: 07/02/2015] [Accepted: 07/21/2015] [Indexed: 12/25/2022]
Affiliation(s)
- Chen Zhu
- Department of Radiation Oncology; The First Affiliated Hospital of Nanjing Medical University; 300 Guangzhou Road Nanjing 210029 China
| | - Qing Xu
- Department of Radiation Oncology; The First Affiliated Hospital of Nanjing Medical University; 300 Guangzhou Road Nanjing 210029 China
| | - Donghui Pan
- Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; 20 Qianrong Road Wuxi 214063 China
| | - Yuping Xu
- Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; 20 Qianrong Road Wuxi 214063 China
| | - Ping Liu
- Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; 20 Qianrong Road Wuxi 214063 China
| | - Runlin Yang
- Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; 20 Qianrong Road Wuxi 214063 China
| | - Lizhen Wang
- Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; 20 Qianrong Road Wuxi 214063 China
| | - Xinchen Sun
- Department of Radiation Oncology; The First Affiliated Hospital of Nanjing Medical University; 300 Guangzhou Road Nanjing 210029 China
| | - Shineng Luo
- Department of Radiation Oncology; The First Affiliated Hospital of Nanjing Medical University; 300 Guangzhou Road Nanjing 210029 China
- Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; 20 Qianrong Road Wuxi 214063 China
| | - Min Yang
- Department of Radiation Oncology; The First Affiliated Hospital of Nanjing Medical University; 300 Guangzhou Road Nanjing 210029 China
- Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; 20 Qianrong Road Wuxi 214063 China
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22
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Abstract
PURPOSE Follicle-stimulating hormone receptor (FSHR) is overexpressed in primary and metastatic tumor. Molecular imaging of FSHR is beneficial for prognosis and therapy of cancer. FSHβ(33-53) (YTRDLVYKDPARPKIQKTCTF), denoted as FSH1, is a FSHR antagonist. In the present study, maleimide-NOTA conjugate of FSH1 (NOTA-MAL-FSH1) was designed and labeled with [(18)F] aluminum fluoride. The resulting tracer, (18)F-Al-NOTA-MAL-FSH1, was preliminarily evaluated in PET imaging of FSHR-positive tumor. PROCEDURES NOTA-MAL-FSH1 was synthesized and radiolabeled with Al(18)F complex. The tumor-targeting potential and pharmacokinetic profile of the (18)F-labeled compound were evaluated in vitro and in vivo using a PC3 human prostate tumor model. RESULTS (18)F-Al-NOTA-MAL-FSH1 can be efficiently produced within 30 min with a non-decay-corrected yield of 48.6 ± 2.1 % and a radiochemical purity of more than 95 %. The specific activity was at least 30 GBq/μmol. The radiotracer was stable in phosphate-buffered saline and human serum for at least 2 h. The IC50 values of displacement (18)F-Al-NOTA-MAL-FSH1 with FSH1 were 252 ± 1.12 nM. The PC3 human prostate tumor xenografts were clearly visible with high contrast after injection of (18)F-Al-NOTA-MAL-FSH1 via microPET. At 30, 60 and 120 min postinjection, the tumor uptakes were 2.98 ± 0.29 % injected dose (ID)/g, 2.53 ± 0.20 %ID/g and 1.36 ± 0.12 %ID/g, respectively. Dynamic PET scanning showed that tumor uptake reached a plateau by about 6 min. Heart peaked earlier and then cleared quickly. Biodistribution studies confirmed that the normal organs except kidney uptakes were all below 1 %ID/g at 1 h p.i. The tumor-to-blood and tumor-to-muscle ratio at 10 min, 0.5, 1, and 2 h after injection were 1.64 ± 0.36, 2.97 ± 0.40, 9.31 ± 1.06, and 13.59 ± 2.33 and 7.05 ± 1.10, 10.10 ± 1.48, 16.17 ± 3.29, and 30.88 ± 4.67, respectively. The tracer was excreted mainly through the renal system, as evidenced by high levels of radioactivity in the kidneys. FSHR-binding specificity was also demonstrated by reduced tumor uptake of (18)F-Al-NOTA-MAL-FSH1 after coinjection with an excess of unlabeled FSH1 peptide. CONCLUSION NOTA-MAL-FSH1 could be labeled rapidly and efficiently with (18)F using one step method. Favorable preclinical data suggest that (18)F-Al-NOTA-MAL-FSH1 may be a suitable radiotracer for the non-invasive visualization of FSHR positive tumor in vivo.
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23
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Usefulness of MRI-assisted metabolic volumetric parameters provided by simultaneous 18F-fluorocholine PET/MRI for primary prostate cancer characterization. Eur J Nucl Med Mol Imaging 2015; 42:1247-56. [DOI: 10.1007/s00259-015-3026-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 02/19/2015] [Indexed: 12/24/2022]
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24
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Yu CY, Desai B, Ji L, Groshen S, Jadvar H. Comparative performance of PET tracers in biochemical recurrence of prostate cancer: a critical analysis of literature. AMERICAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 2014; 4:580-601. [PMID: 25250207 PMCID: PMC4171844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 07/12/2014] [Accepted: 07/21/2014] [Indexed: 06/03/2023]
Abstract
Positron emission tomography (PET) with a number of tracers targeted to particular biological features of cancer has been explored for the imaging evaluation of patients with biochemical recurrence of prostate cancer after curative primary treatment. However, these reports are often heterogeneous in study design, patient cohorts, standards of reference for the imaging findings, data analysis, and data reporting. The aim of our study was to address these limitations by extracting and re-analyzing the PET detection data only from studies that satisfied pre-defined sets of patient selection criteria and verification standards. Our investigation analyzed the effects of 5 tracers ((18)F-fluorodeoxyglucose (FDG), (11)C-acetate (ACET), (11)C- or (18)F-choline (CHOL), anti-1-amino-3-(18)F-fluorocyclobutane-1-carboxylic acid (FACBC), and radiolabeled ligand targeted to prostate-specific membrane antigen (PSMA)), 2 treatment types (radical prostatectomy and radiation therapy), and whether the detected disease was local or metastatic, including lesion type (bone, lymph node, soft tissue). FDG exhibited the lowest detection rate for any suspected disease. ACET tended to be advantageous over CHOL in detecting local recurrence and lymph node lesions, even though the difference was not statistically significant. FACBC had greater likelihood of detecting local recurrence, when compared to CHOL, though this difference was not statistically significant. PSMA tended to show a higher proportion of patients with suspected disease compared to the other four tracers. Patients treated with radiation therapy had greater odds of displaying local recurrence on PET than those treated with radical prostatectomy. We also provide suggestions for future investigations that facilitate communication and the impact of the findings.
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Affiliation(s)
- Chung Yao Yu
- Department of Radiology, Keck School of Medicine of USC, University of Southern CaliforniaLos Angeles, CA, USA
| | - Bhushan Desai
- Department of Radiology, Keck School of Medicine of USC, University of Southern CaliforniaLos Angeles, CA, USA
| | - Lingyun Ji
- Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern CaliforniaLos Angeles, CA, USA
| | - Susan Groshen
- Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern CaliforniaLos Angeles, CA, USA
| | - Hossein Jadvar
- Department of Radiology, Keck School of Medicine of USC, University of Southern CaliforniaLos Angeles, CA, USA
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25
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Nayak TR, Hong H, Zhang Y, Cai W. Multimodality imaging of CXCR4 in cancer: current status towards clinical translation. Curr Mol Med 2014; 13:1538-48. [PMID: 24206137 DOI: 10.2174/1566524013666131111121325] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2012] [Revised: 04/02/2012] [Accepted: 09/10/2013] [Indexed: 12/17/2022]
Abstract
CXCR4 has gained tremendous attention over the last decade, since it was found to be up-regulated in a wide variety of cancer types, in addition to its role in human immunodeficiency virus infection. Molecular imaging of CXCR4 with small molecules, peptides, and antibodies has been a vibrant research area over the last several years. In this review article, we will summarize the current status of imaging CXCR4 with fluorescence, bioluminescence, positron emission tomography, and single-photon emission computed tomography techniques. Since each molecular imaging modality has its own strengths and weaknesses, dualmodality probes that can be detected by more than one imaging techniques have also been investigated. Noninvasive visualization of CXCR4 expression has potential clinical applications in multiple facets of patient management. While big strides have been made over the last several years in the development of CXCR4- targeted imaging probes, clinical translation and investigation of these agents in cancer patients are eagerly awaited. Since CXCR4 is also involved in many other diseases beyond cancer, these clinically translatable probes can also play multiple roles in other pathological disorders such as myocardial infarction and several immunodeficiency disorders.
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Affiliation(s)
- T R Nayak
- Departments of Radiology and Medical Physics, University of Wisconsin - Madison, Room 7137, 1111 Highland Avenue, Madison, WI 53705-2275, USA.
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Pan D, Yan Y, Yang R, Xu YP, Chen F, Wang L, Luo S, Yang M. PET imaging of prostate tumors with 18F-Al-NOTA-MATBBN. CONTRAST MEDIA & MOLECULAR IMAGING 2014; 9:342-8. [PMID: 24729577 DOI: 10.1002/cmmi.1583] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Revised: 09/30/2013] [Accepted: 10/24/2013] [Indexed: 12/12/2022]
Abstract
Overexpression of the gastrin-releasing peptide receptor (GRPR) in prostate cancer provides a promising target for detection the disease. MATBBN is a new bombesin analog originating from the GRPR antagonists with a hydrophilic linker. In this study NOTA-conjugated MATBBN was labeled by the Al(18)F method and the potential of (18)F-Al-NOTA-MATBBN for prostate tumor PET imaging was also evaluated. NOTA-MATBBN was radiolabeled with (18) F using Al(18)F complexes. Partition coefficient, in vitro stability and GRPR binding affinity were also determined. PET studies were performed with (18)F-Al-NOTA-MATBBN in PC-3 tumor-bearing mice. (18)F-Al-NOTA-MATBBN can be produced within 30 min with a decay-corrected yield of 62.5 ± 2.1% and a radiochemical purity of >98%. The logP octanol-water value for the Al(18)F-labeled BBN analog was -2.40 ± 0.07 and the radiotracer was stable in phosphate-buffered saline and human serum for 2 h. The IC50 values of displacement for the (18)F-Al-NOTA-MATBBN with MATBBN was 126.9 ± 2.75 nm. The PC-3 tumors were clearly visible with high contrast after injection of the labeled peptide. At 60 min post-injection, the tumor uptakes for (18)F-Al-NOTA-MATBBN and (18)F-FDG were 4.59 ± 0.43 and 1.98 ± 0.35% injected dose/g, and tumor to muscle uptake radios for two tracers were 6.77 ± 1.10 and 1.78 ± 0.32, respectively. Dynamic PET revealed that (18) F-Al-NOTA-MATBBN was excreted mainly through the kidneys. GRPR-binding specificity was also demonstrated by reduced tumor uptake of (18)F-Al-NOTA-MATBBN after coinjection with excess unlabeled MATBBN peptide at 1 h post-injection. NOTA- MATBBN could be labeled rapidly with (18)F using one step method. (18)F-Al-NOTA-MATBBN may be a promising PET imaging agent for prostate cancer.
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Affiliation(s)
- Donghui Pan
- Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, 214063, China
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Zaorsky NG, Yamoah K, Thakur ML, Trabulsi EJ, Showalter TN, Hurwitz MD, Dicker AP, Den RB. A paradigm shift from anatomic to functional and molecular imaging in the detection of recurrent prostate cancer. Future Oncol 2014; 10:457-74. [PMID: 24559451 PMCID: PMC6615465 DOI: 10.2217/fon.13.196] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Approximately a third of men with localized prostate cancer who are treated with external beam radiation therapy (EBRT) or radical prostatectomy (RP) develop biochemical failure (BF). Presumably, BF will progress to distant metastasis and prostate cancer-specific mortality in some patients over subsequent years. Accurate detection of recurrent disease is important because it allows for appropriate treatment selection (e.g., local vs systemic therapy) and early delivery of therapy (e.g., salvage EBRT), which affect patient outcome. In this article, we discuss the paradigm shift in imaging technology in the detection of recurrent prostate cancer. First, we discuss the commonly used morphological and anatomical imaging modalities and their role in the post-RP and post-EBRT settings of BF. Second, we discuss the accuracy of functional and molecular imaging techniques, many of which are under investigation. Further studies are needed to establish the role of imaging techniques for detection of cancer recurrence and clinical decision-making.
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Affiliation(s)
- Nicholas G Zaorsky
- Department of Radiation Oncology, Fox Chase Cancer Center, PA, USA
- Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, PA, USA
| | - Kosj Yamoah
- Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, PA, USA
| | - Madhukar L Thakur
- Department of Radiology, Jefferson Medical College of Thomas Jefferson University, PA, USA
| | - Edouard J Trabulsi
- Department of Urology, Jefferson Medical College of Thomas Jefferson University, PA, USA
| | - Timothy N Showalter
- Department of Radiation Oncology, University of Virginia, Charlottesville, PA, USA
| | - Mark D Hurwitz
- Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, PA, USA
| | - Adam P Dicker
- Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, PA, USA
| | - Robert B Den
- Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, PA, USA
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28
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Bergmann R, Ruffani A, Graham B, Spiccia L, Steinbach J, Pietzsch J, Stephan H. Synthesis and radiopharmacological evaluation of 64Cu-labeled bombesin analogs featuring a bis(2-pyridylmethyl)-1,4,7-triazacyclononane chelator. Eur J Med Chem 2013; 70:434-46. [DOI: 10.1016/j.ejmech.2013.10.013] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Revised: 08/26/2013] [Accepted: 10/05/2013] [Indexed: 12/25/2022]
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Bi X, Sterling JA, Merkel AR, Perrien DS, Nyman JS, Mahadevan-Jansen A. Prostate cancer metastases alter bone mineral and matrix composition independent of effects on bone architecture in mice--a quantitative study using microCT and Raman spectroscopy. Bone 2013; 56:454-60. [PMID: 23867219 PMCID: PMC3799839 DOI: 10.1016/j.bone.2013.07.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2012] [Revised: 02/22/2013] [Accepted: 07/04/2013] [Indexed: 11/25/2022]
Abstract
Prostate cancer is the most common primary tumor and the second leading cause of cancer-related deaths in men in the United States. Prostate cancer bone metastases are characterized by abnormal bone remodeling processes and result in a variety of skeletal morbidities. Prevention of skeletal complications is a crucial element in prostate cancer management. This study investigated prostate cancer-induced alterations in the molecular composition and morphological structure of metastasis-bearing bones in a mouse model of prostate cancer using Raman spectroscopy and micro-computed tomography (microCT). LNCaP C4-2B prostate cancer cells were injected into the right tibiae of 5-week old male SCID mice. Upon sacrifice at 8weeks post tumor inoculation, two out of the ten tumor-bearing tibiae showed only osteoblastic lesions in the radiographs, 4 osteolytic lesions only and 4 mixed with osteoblastic and osteolytic lesions. Carbonate substitution was significantly increased while there was a marked reduction in the level of collagen mineralization, mineral crystallinity, and carbonate:matrix ratio in the cortex of the intact tumor-bearing tibiae compared to contralateral controls. MicroCT analysis revealed a significant reduction in bone volume/total volume, trabecular number and trabecular thickness, as well as significant increase in bone surface/volume ratio in tibiae with osteolytic lesions, suggesting active bone remodeling and bone loss. None of the changes in bone compositional properties were correlated with lesion area from radiographs or the changes in bone architecture from microCT. This study indicates that LNCaP C4-2B prostate cancer metastases alter bone tissue composition independent of changes in architecture, and altered bone quality may be an important contributor to fracture risk in these patients. Raman spectroscopy may provide a new avenue of investigation into interactions between tumor and bone microenvironment.
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Affiliation(s)
- Xiaohong Bi
- Department of Biomedical Engineering, Vanderbilt University, VU Station B#351631, 2301 Vanderbilt Place, Nashville, TN 37235, USA.
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30
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McParland BJ, Wall A, Johansson S, Sørensen J. The clinical safety, biodistribution and internal radiation dosimetry of [18F]fluciclovine in healthy adult volunteers. Eur J Nucl Med Mol Imaging 2013; 40:1256-64. [DOI: 10.1007/s00259-013-2403-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Accepted: 03/19/2013] [Indexed: 11/29/2022]
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Ma J, Huang F, Lin H, Wang X. Isolation and purification of a peptide from Bullacta exarata and its impaction of apoptosis on prostate cancer cell. Mar Drugs 2013; 11:266-73. [PMID: 23344115 PMCID: PMC3564171 DOI: 10.3390/md11010266] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Revised: 12/20/2012] [Accepted: 12/24/2012] [Indexed: 12/23/2022] Open
Abstract
Bullacta exarata was hydrolyzed with trypsin to prepare peptides; Hydrolysates were isolated by ultrafiltration and purified using G-25 gel filtration. The purity of the Bullacta exarata was demonstrated by HPLC and its peptide sequence analysis was detected. The effects of BEPT II and BEPT II-1 on the proliferation of PC-3 cells were examined using a MTT assay. BEPT II and BEPT II-1 significantly inhibited the proliferation of PC-3 cells in a time- and dose-dependent manner. Annexin V/PI double staining studies showed exposing PC-3 cells to 5, or 15 mg/mL BEPT II-1 for 24 h increased the percentage of the early stage of apoptotic cells from 11.22% to 22.09%. In addition, typical morphologic changes were observed in the cells with acridine orange/ethidium bromide staining. These data support that BEPT II-1 has anticancer properties and merits further investigation to understand the mechanisms of BEPT II-1-induced apoptosis in PC-3 cells.
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Affiliation(s)
- Jianyin Ma
- School of Food Science and Pharmacy, Zhejiang Provincial Key Engineering Technology Research Center of Marine Biomedical Products, Zhejiang Ocean University, Zhoushan 316000, China.
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33
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Schuster DM, Taleghani PA, Nieh PT, Master VA, Amzat R, Savir-Baruch B, Halkar RK, Fox T, Osunkoya AO, Moreno CS, Nye JA, Yu W, Fei B, Wang Z, Chen Z, Goodman MM. Characterization of primary prostate carcinoma by anti-1-amino-2-[(18)F] -fluorocyclobutane-1-carboxylic acid (anti-3-[(18)F] FACBC) uptake. AMERICAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 2013; 3:85-96. [PMID: 23342303 PMCID: PMC3545368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 10/07/2012] [Accepted: 12/10/2012] [Indexed: 06/01/2023]
Abstract
Anti-1-amino-3-[(18)F] fluorocyclobutane-1-carboxylic acid (anti-3-[(18)F] FACBC) is a synthetic amino acid positron emission tomography (PET) radiotracer with utility in the detection of recurrent prostate carcinoma. The aim of this study is to correlate uptake of anti-3-[(18)F] FACBC with histology of prostatectomy specimens in patients undergoing radical prostatectomy and to determine if uptake correlates to markers of tumor aggressiveness such as Gleason score. Ten patients with prostate carcinoma pre-radical prostatectomy underwent 45 minute dynamic PET-CT of the pelvis after IV injection of 347.8 ± 81.4 MBq anti-3-[(18)F] FACBC. Each prostate was co-registered to a separately acquired MR, divided into 12 sextants, and analyzed visually for abnormal focal uptake at 4, 16, 28, and 40 min post-injection by a single reader blinded to histology. SUVmax per sextant and total sextant activity (TSA) was also calculated. Histology and Gleason scores were similarly recorded by a urologic pathologist blinded to imaging. Imaging and histologic analysis were then compared. In addition, 3 representative sextants from each prostate were chosen based on highest, lowest and median SUVmax for immunohistochemical (IHC) analysis of Ki67, synaptophysin, P504s, chromogranin A, P53, androgen receptor, and prostein. 79 sextants had malignancy and 41 were benign. Highest combined sensitivity and specificity was at 28 min by visual analysis; 81.3% and 50.0% respectively. SUVmax was significantly higher (p<0.05) for malignant sextants (5.1±2.6 at 4 min; 4.5±1.6 at 16 min; 4.0±1.3 at 28 min; 3.8±1.0 at 40 min) compared to non-malignant sextants (4.0±1.9 at 4 min; 3.5±0.8 at 16 min; 3.4±0.9 at 28 min; 3.3±0.9 at 40 min), though there was overlap of activity between malignant and non-malignant sextants. SUVmax also significantly correlated (p<0.05) with Gleason score at all time points (r=0.28 at 4 min; r=0.42 at 16 min; r=0.46 at 28 min; r=0.48 at 40 min). There was no significant correlation of anti-3-[(18)F] FACBC SUVmax with Ki-67 or other IHC markers. Since there was no distinct separation between malignant and non-malignant sextants or between Gleason score levels, we believe that anti-3-[(18)F] FACBC PET should not be used alone for radiation therapy planning but may be useful to guide biopsy to the most aggressive lesion.
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Affiliation(s)
- David M Schuster
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA, USA
| | - Pooneh A Taleghani
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA, USA
| | - Peter T Nieh
- Department of Urology, Emory UniversityAtlanta, GA, USA
| | | | - Rianot Amzat
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA, USA
| | - Bital Savir-Baruch
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA, USA
| | - Raghuveer K Halkar
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA, USA
| | - Tim Fox
- Department of Radiation Oncology, Emory UniversityAtlanta, GA, USA
| | - Adeboye O Osunkoya
- Department of Urology, Emory UniversityAtlanta, GA, USA
- Pathology and Laboratory Medicine, Emory UniversityAtlanta, GA, USA
| | - Carlos S Moreno
- Pathology and Laboratory Medicine, Emory UniversityAtlanta, GA, USA
| | - Jonathon A Nye
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA, USA
| | - Weiping Yu
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA, USA
| | - Baowei Fei
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA, USA
| | - Zhibo Wang
- Department of Biostatistics and Bioinformatics, Emory UniversityAtlanta, GA, USA
| | - Zhengjia Chen
- Department of Biostatistics and Bioinformatics, Emory UniversityAtlanta, GA, USA
| | - Mark M Goodman
- Department of Radiology and Imaging Sciences, Emory UniversityAtlanta, GA, USA
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Mease RC, Foss CA, Pomper MG. PET imaging in prostate cancer: focus on prostate-specific membrane antigen. Curr Top Med Chem 2013. [PMID: 23590171 DOI: 10.2174/092986712] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/27/2023]
Abstract
Prostate cancer (PCa) is the second leading cause of cancer-related death in American men. Positron emission tomography/computed tomography (PET/CT) with emerging radiopharmaceuticals promises accurate staging of primary disease, restaging of recurrent disease, detection of metastatic lesions and, ultimately, for predicting the aggressiveness of disease. Prostate-specific membrane antigen (PSMA) is a well-characterized imaging biomarker of PCa. Because PSMA levels are directly related to androgen independence, metastasis and progression, PSMA could prove an important target for the development of new radiopharmaceuticals for PET. Preclinical data for new PSMA-based radiotracers are discussed and include new (89)Zr- and (64)Cu-labeled anti-PSMA antibodies and antibody fragments, (64)Cu-labeled aptamers, and (11)C-, (18)F-, (68)Ga-, (64)Cu-, and (86)Y-labeled low molecular weight inhibitors of PSMA. Several of these agents, namely (68)Ga- HBED-CC conjugate 15, (18)F-DCFBC 8, and BAY1075553 are particularly promising, each having detected sites of PCa in initial clinical studies. These early clinical results suggest that PET/CT using PSMA-targeted agents, especially with compounds of low molecular weight, will make valuable contributions to the management of PCa.
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Affiliation(s)
- Ronnie C Mease
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical School, Baltimore, MD 21287, USA
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35
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RGD-Binding Integrins in Prostate Cancer: Expression Patterns and Therapeutic Prospects against Bone Metastasis. Cancers (Basel) 2012; 4:1106-45. [PMID: 24213501 PMCID: PMC3712721 DOI: 10.3390/cancers4041106] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Revised: 10/09/2012] [Accepted: 10/22/2012] [Indexed: 12/26/2022] Open
Abstract
Prostate cancer is the third leading cause of male cancer deaths in the developed world. The current lack of highly specific detection methods and efficient therapeutic agents for advanced disease have been identified as problems requiring further research. The integrins play a vital role in the cross-talk between the cell and extracellular matrix, enhancing the growth, migration, invasion and metastasis of cancer cells. Progression and metastasis of prostate adenocarcinoma is strongly associated with changes in integrin expression, notably abnormal expression and activation of the β3 integrins in tumour cells, which promotes haematogenous spread and tumour growth in bone. As such, influencing integrin cell expression and function using targeted therapeutics represents a potential treatment for bone metastasis, the most common and debilitating complication of advanced prostate cancer. In this review, we highlight the multiple ways in which RGD-binding integrins contribute to prostate cancer progression and metastasis, and identify the rationale for development of multi-integrin antagonists targeting the RGD-binding subfamily as molecularly targeted agents for its treatment.
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Abstract
OBJECTIVE Recent advances in the fundamental understanding of the complex biology of prostate cancer have provided an increasing number of potential targets for imaging and treatment. The imaging evaluation of prostate cancer needs to be tailored to the various phases of this remarkably heterogeneous disease. CONCLUSION In this article, I review the current state of affairs on a range of PET radiotracers for potential use in the imaging evaluation of men with prostate cancer.
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Sepia ink oligopeptide induces apoptosis in prostate cancer cell lines via caspase-3 activation and elevation of Bax/Bcl-2 ratio. Mar Drugs 2012; 10:2153-2165. [PMID: 23170075 PMCID: PMC3497014 DOI: 10.3390/md10102153] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2012] [Revised: 08/18/2012] [Accepted: 09/07/2012] [Indexed: 11/17/2022] Open
Abstract
Sepia ink oligopeptide (SIO) is a tripeptide extracted from Sepia ink. To test the hypothesis that SIO inhibits prostate cancer by inducing apoptosis, the effects of SIO on the proliferation of three human prostate cancer cell lines were examined using a CCK-8 assay. SIO significantly inhibited the proliferation of DU-145, PC-3 and LNCaP cells in a time- and dose-dependent manner. Flow cytometry studies showed that exposing DU-145, PC-3 and LNCaP cells to 5, 10, or 15 mg/mL SIO for 24 h increased the percentage of the early-stage apoptotic cells from 11.84% to 38.26% (DU-145), 22.76% to 39.96% (PC-3) and 5.05% to 16.11% (LNCaP), respectively. In addition, typical morphologic changes were observed in the cells with acridine orange/ethidium bromide staining. SIO treatment induced strong S and G2/M phase cell cycle arrest in a dose-dependent manner in DU-145 and LNCaP. In contrast, SIO treatment induced strong Sub G1 and G0/G1 phase cell cycle arrest in a dose-dependent manner in PC-3. SIO exposure for 24 h decreased the expression of the anti-apoptotic protein Bcl-2 and increased the expression of the apoptogenic protein Bax. Moreover, the Bax/Bcl-2expression ratio was increased. Concurrently, the expression of caspase-3 was upregulated. These data support our hypothesis that SIO has anticarcinogenic properties.
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Lütje S, Boerman OC, van Rij CM, Sedelaar M, Helfrich W, Oyen WJG, Mulders PFA. Prospects in radionuclide imaging of prostate cancer. Prostate 2012; 72:1262-72. [PMID: 22127918 DOI: 10.1002/pros.22462] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2011] [Accepted: 10/31/2011] [Indexed: 11/07/2022]
Abstract
Prostate cancer is the most common malignancy in men in the Western world and represents a major health problem with substantial morbidity and mortality. Sensitivity and specificity of digital rectal examination (DRE) and evaluation of prostate specific antigen (PSA) are excellent methods for diagnosis of prostate cancer, but have limited value for staging. Imaging of prostate cancer has become increasingly important to improve staging and management of prostate cancer patients. Conventional imaging modalities, such as transrectal ultrasound and computed tomography, show limited accuracy for a reliable assessment of prostate cancer. Diagnostic value of magnetic resonance imaging has improved by dynamic contrast enhancement (DCI-MRI) and diffusion-weighted magnetic resonance imaging (DWI). Recently, substantial progress has been made in the development of functional and molecular imaging modalities, such as positron emission tomography using radiolabeled metabolic tracers, receptor-binding ligands, amino acids, peptides, or antibodies. Here, we review the value of these novel radionuclide imaging techniques in the assessment of prostate cancer.
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Affiliation(s)
- Susanne Lütje
- Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
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James ML, Gambhir SS. A molecular imaging primer: modalities, imaging agents, and applications. Physiol Rev 2012; 92:897-965. [PMID: 22535898 DOI: 10.1152/physrev.00049.2010] [Citation(s) in RCA: 736] [Impact Index Per Article: 56.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Molecular imaging is revolutionizing the way we study the inner workings of the human body, diagnose diseases, approach drug design, and assess therapies. The field as a whole is making possible the visualization of complex biochemical processes involved in normal physiology and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on molecular imaging of intact living subjects. We provide a basic primer for those who are new to molecular imaging, and a resource for those involved in the field. We begin by describing classical molecular imaging techniques together with their key strengths and limitations, after which we introduce some of the latest emerging imaging modalities. We provide an overview of the main classes of molecular imaging agents (i.e., small molecules, peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how molecular imaging is being applied in oncology, neuroscience, cardiology, gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biological and/or clinical questions using the tools of molecular imaging is also provided. We conclude by discussing the grand challenges of the field, its future directions, and enormous potential for further impacting how we approach research and medicine.
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Affiliation(s)
- Michelle L James
- Molecular Imaging Program, Department of Radiology, Stanford University, Palo Alto, CA 94305, USA
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40
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Taylor RM, Severns V, Brown DC, Bisoffi M, Sillerud LO. Prostate cancer targeting motifs: expression of αν β3, neurotensin receptor 1, prostate specific membrane antigen, and prostate stem cell antigen in human prostate cancer cell lines and xenografts. Prostate 2012; 72:523-32. [PMID: 21748756 PMCID: PMC4366051 DOI: 10.1002/pros.21454] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2011] [Accepted: 06/15/2011] [Indexed: 12/28/2022]
Abstract
BACKGROUND Membrane receptors are frequent targets of cancer therapeutic and imaging agents. However, promising in vitro results often do not translate to in vivo clinical applications. To better understand this obstacle, we measured the expression differences in receptor signatures among several human prostate cancer cell lines and xenografts as a function of tumorigenicity. METHODS Messenger RNA and protein expression levels for integrin α(ν) β(3), neurotensin receptor 1 (NTSR1), prostate specific membrane antigen (PSMA), and prostate stem cell antigen (PSCA) were measured in LNCaP, C4-2, and PC-3 human prostate cancer cell lines and in murine xenografts using quantitative reverse transcriptase polymerase chain reaction, flow cytometry, and immunohistochemistry. RESULTS Stable expression patterns were observed for integrin α(ν) and PSMA in all cells and corresponding xenografts. Integrin β(3) mRNA expression was greatly reduced in C4-2 xenografts and greatly elevated in PC-3 xenografts compared with the corresponding cultured cells. NTSR1 mRNA expression was greatly elevated in LNCaP and PC-3 xenografts. PSCA mRNA expression was elevated in C4-2 xenografts when compared with C4-2 cells cultured in vitro. Furthermore, at the protein level, PSCA was re-expressed in all xenografts compared with cells in culture. CONCLUSIONS The regulation of mRNA and protein expression of the cell-surface target proteins α(ν) β(3), NTSR1, PSMA, and PSCA, in prostate cancer cells with different tumorigenic potential, was influenced by factors of the microenvironment, differing between cell cultures and murine xenotransplants. Integrin α(ν) β(3), NTRS1 and PSCA mRNA expression increased with tumorigenic potential, but mRNA expression levels for these proteins do not translate directly to equivalent expression levels of membrane bound protein.
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Affiliation(s)
- Robert M Taylor
- Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
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Hall MA, Kwon S, Robinson H, Lachance PA, Azhdarinia A, Ranganathan R, Price RE, Chan W, Sevick-Muraca EM. Imaging prostate cancer lymph node metastases with a multimodality contrast agent. Prostate 2012; 72:129-46. [PMID: 21538422 DOI: 10.1002/pros.21413] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Accepted: 04/06/2011] [Indexed: 01/05/2023]
Abstract
BACKGROUND Methods to detect lymph node (LN) metastases in prostate cancer (PCa) are limited. Pelvic LN dissection is commonly performed during prostatectomy, but often followed by morbid complications. More refined methods for detecting LN invasion are needed. METHODS We developed a dual-labeled targeting agent having a near-infrared (NIR) fluorophore for intraoperative guidance, and a conventional radiotracer for detection of LN metastasis. Nu/Nu mice were orthotopically implanted with DsRed-expressing human PCa (PC3) cells. Antibody (Ab) specific for epithelial cell adhesion molecule was conjugated to DOTA, IRDye 800CW, and radiolabeled with (64) Cu. Dual-labeled Ab was administered intravenously at 10-12 weeks post-implantation, and positron emission tomography/computed tomography (PET/CT) and fluorescence imaging were performed within 18-24 hr. RESULTS Metastasis to lumbar LNs was detected by DsRed fluorescence imaging, as well as pathology, in 75% of mice having pathology-confirmed primary prostate tumors. These metastases were also detected by NIR fluorescence imaging. In some cases, metastases to sciatic, medial, renal, and axillary nodes were also detected. For all LNs examined, no significant differences were found between the percentages of metastases detected by NIR imaging (63%) and µPET/CT (64%) (P = 0.93), or between those detected by DsRed imaging (25%) and pathological examination (19%) (P = 0.12). CONCLUSION This study demonstrates that a multimodality contrast agent is useful for early detection of metastatic disease, and has applications for intraoperative PCa treatment. Further agent optimization is necessary to enhance specificity, and provide validation for prostate and other LN metastasizing epithelial cancers.
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Affiliation(s)
- Mary A Hall
- Center for Molecular Imaging, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, USA
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Graham MM. Clinical molecular imaging with radiotracers: current status. Med Princ Pract 2012; 21:197-208. [PMID: 22142905 DOI: 10.1159/000333552] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2011] [Accepted: 09/05/2011] [Indexed: 12/17/2022] Open
Abstract
Molecular imaging is defined as the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems. Most clinical molecular imaging is currently done using radioisotope-labeled agents to define the activity of various metabolic pathways in vivo or to determine the distribution and density of various receptors relevant to human disease. This paper briefly reviews most of the commonly used radiopharmaceuticals in nuclear medicine, as well as newer agents that are likely to become available in the near future. The metabolic pathways include those relevant to the thyroid, parathyroid, heart, brain, bones, kidneys, liver, pancreas, adrenals and tumor. The receptor systems include agents useful in evaluating movement disorders, dementia, cardiac sympathetic enervation and neoangiogenesis. Receptor systems relevant to tumors include somatostatin receptors (neuroendocrine tumors), prostate-specific membrane antigen, carbonic anhydrase IX (renal cancer), and CD-20 (lymphoma). These agents, and newer agents that are being developed, are likely to become critical in the development of personalized medicine, where it will become increasingly important to determine whether a treatment that is targeted to a specific metabolic pathway or receptor is likely to be successful.
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Affiliation(s)
- Michael M Graham
- Department of Radiology, University of Iowa, Iowa City, Iowa, USA.
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Affiliation(s)
- Xiaoyuan Chen
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), 31 Center Dr, 1C22, Bethesda, MD 20892-2281, USA
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King GF. Venoms as a platform for human drugs: translating toxins into therapeutics. Expert Opin Biol Ther 2011; 11:1469-84. [PMID: 21939428 DOI: 10.1517/14712598.2011.621940] [Citation(s) in RCA: 392] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION An extraordinarily diverse range of animals have evolved venoms for predation, defence, or competitor deterrence. The major components of most venoms are peptides and proteins that are often protease-resistant due to their disulfide-rich architectures. Some of these toxins have become valuable as pharmacological tools and/or therapeutics due to their extremely high specificity and potency for particular molecular targets. There are currently six FDA-approved drugs derived from venom peptides or proteins. AREAS COVERED This article surveys the current pipeline of venom-derived therapeutics and critically examines the potential of peptide and protein drugs derived from venoms. Emerging trends are identified, including an increasing industry focus on disulfide-rich venom peptides and the use of a broader array of molecular targets in order to develop venom-based therapeutics for treating a wider range of clinical conditions. EXPERT OPINION Key technical advances in combination with a renewed industry-wide focus on biologics have converged to provide a larger than ever pipeline of venom-derived therapeutics. Disulfide-rich venom peptides obviate some of the traditional disadvantages of therapeutic peptides and some may be suitable for oral administration. Moreover, some venom peptides can breach the blood brain barrier and translocate across cell membranes, which opens up the possibility of exploiting molecular targets not previously accessible to peptide drugs.
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Affiliation(s)
- Glenn F King
- The University of Queensland, Institute for Molecular Bioscience, 306 Carmody Road, St Lucia, Queensland 4072, Australia.
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Kukuk D, Reischl G, Raguin O, Wiehr S, Judenhofer MS, Calaminus C, Honndorf VS, Quintanilla-Martinez L, Schönberger T, Duchamp O, Machulla HJ, Pichler BJ. Assessment of PET tracer uptake in hormone-independent and hormone-dependent xenograft prostate cancer mouse models. J Nucl Med 2011; 52:1654-63. [PMID: 21859811 DOI: 10.2967/jnumed.110.086702] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
UNLABELLED The pharmacokinetics of (18)F-fluorodeoxythymidine (FLT), (18)F-FDG, (11)C-choline, and (18)F-fluoroethylcholine (FEC) in 2 hormone-independent (PC-3, DU145) and 2 hormone-dependent (CWR22, PAC120) prostate cancer xenograft mouse models were evaluated by PET and compared by immunohistochemistry. Further investigation was performed to determine whether PET can detect early changes in tumor metabolism after androgen ablation therapy through surgical castration. METHODS PET was performed on 4 consecutive days. In addition, the CWR22 and PAC120 tumor models were surgically castrated after the baseline measurement and imaged again after castration. The tracer uptake was analyzed using time-activity curves, percentage injected dose per volume (%ID/cm(3)), and tumor-to-muscle ratio (T/M). RESULTS Regarding the hormone-independent prostate tumor models, (18)F-FLT showed the best T/M and highest %ID/cm(3) in PC-3 (2.97 ± 0.63 %ID/cm(3)) and DU145 (2.06 ± 0.75 %ID/cm(3)) tumors. (18)F-FDG seemed to be the tracer of choice for delineation of the PC-3 tumors but not for the DU145 tumors. Using (11)C-choline (PC-3: 1.33 ± 0.29 %ID/cm(3), DU145: 1.60 ± 0.27 %ID/cm(3)) and (18)F-FEC, we did not find any significant uptake in the tumors, compared with muscle tissue. Regarding the hormone-dependent prostate tumor models, the CWR22 model showed a highly significant (P < 0.01) decrease in tumor (18)F-FDG uptake from 4.11 ± 1.29 %ID/cm(3) to 2.19 ± 1.45 %ID/cm(3) after androgen ablation therapy. However, the (18)F-FLT, (11)C-choline, or (18)F-FEC tracers did not provide sufficient uptake or reliable information about therapy response in CWR22 tumors. The PAC120 model showed a significant increase in (18)F-FLT tumor uptake (P = 0.015) after androgen ablation therapy. The accumulation of (18)F-FEC (before: 2.32 ± 1.01 %ID/cm(3), after: 1.36 ± 0.39 %ID/cm(3)) was found to be the next highest after (18)F-FDG (before: 2.45 ± 0.93 %ID/cm(3), after: 2.18 ± 0.65 %ID/cm(3)) in PAC120 tumors before castration and is better suited for monitoring therapy response. CONCLUSION This comprehensive study in 2 hormone-dependent and 2 hormone-independent prostate tumor mouse models shows that (18)F-FLT and (18)F-FDG are the most appropriate tracers for delineation of PC-3, DU145 (except (18)F-FDG), and CWR22 tumors, but not for PAC120 tumors. (18)F-FEC and (11)C-choline, in particular, revealed insufficient T/M ratio in the prostate tumor models. The results may indicate that radiolabeled choline and choline derivatives compete with a high concentration of the precursor dimethylaminoethanol, resulting in reduced uptake in small-rodent tumor models, a hypothesis that is currently under investigation in our laboratory.
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Affiliation(s)
- Damaris Kukuk
- Department of Preclinical Imaging and Radiopharmacy, Laboratory for Preclinical Imaging and Imaging Technology of the Werner Siemens-Foundation, Eberhard Karls University, Tübingen, Germany
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Ananias HJK, Yu Z, Dierckx RA, van der Wiele C, Helfrich W, Wang F, Yan Y, Chen X, de Jong IJ, Elsinga PH. 99mTechnetium-HYNIC(tricine/TPPTS)-Aca-Bombesin(7–14) as a Targeted Imaging Agent with MicroSPECT in a PC-3 Prostate Cancer Xenograft Model. Mol Pharm 2011; 8:1165-73. [DOI: 10.1021/mp200014h] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Hildo J. K. Ananias
- Department of Urology, University Medical Center Groningen, Groningen, The Netherlands
| | - Zilin Yu
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands
| | - Rudi A. Dierckx
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Wijnand Helfrich
- Surgical Research Laboratory, University Medical Center Groningen, Groningen, The Netherlands
| | - Fan Wang
- Medical Isotopes Research Center, Peking University, Peking, China
| | - Yongjun Yan
- Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, United States
| | - Xiaoyuan Chen
- Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, United States
| | - Igle J. de Jong
- Department of Urology, University Medical Center Groningen, Groningen, The Netherlands
| | - Philip H. Elsinga
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands
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Schuster DM, Savir-Baruch B, Nieh PT, Master VA, Halkar RK, Rossi PJ, Lewis MM, Nye JA, Yu W, Bowman FD, Goodman MM. Detection of recurrent prostate carcinoma with anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid PET/CT and 111In-capromab pendetide SPECT/CT. Radiology 2011; 259:852-61. [PMID: 21493787 DOI: 10.1148/radiol.11102023] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
PURPOSE To compare the diagnostic performance of the synthetic amino acid analog radiotracer anti-1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid (anti-3-(18)F-FACBC) with that of indium 111 ((111)In)-capromab pendetide in the detection of recurrent prostate carcinoma. MATERIALS AND METHODS This prospective study was approved by the institutional review board and complied with HIPAA guidelines. Written informed consent was obtained. Fifty patients (mean age, 68.3 years ± 8.1 [standard deviation]; age range, 50-90 years) were included in the study on the basis of the following criteria: (a) Recurrence of prostate carcinoma was suspected after definitive therapy for localized disease, (b) bone scans were negative, and (c) anti-3-(18)F-FACBC positron emission tomography (PET)/computed tomography (CT) and (111)In-capromab pendetide single photon emission computed tomography (SPECT)/CT were performed within 6 weeks of each other. Studies were evaluated by two experienced interpreters for abnormal uptake suspicious for recurrent disease in the prostate bed and extraprostatic locations. The reference standard was a combination of tissue correlation, imaging, laboratory, and clinical data. Diagnostic performance measures were calculated and tests of the statistical significance of differences determined by using the McNemar χ(2) test as well as approximate tests based on the difference between two proportions. RESULTS For disease detection in the prostate bed, anti-3-(18)F-FACBC had a sensitivity of 89% (32 of 36 patients; 95% confidence interval [CI]: 74%, 97%), specificity of 67% (eight of 12 patients; 95% CI: 35%, 90%), and accuracy of 83% (40 of 48 patients; 95% CI: 70%, 93%). (111)In-capromab pendetide had a sensitivity of 69% (25 of 36 patients; 95% CI: 52%, 84%), specificity of 58% (seven of 12 patients; 95% CI: 28%, 85%), and accuracy of 67% (32 of 48 patients; 95% CI: 52%, 80%). In the detection of extraprostatic recurrence, anti-3-(18)F-FACBC had a sensitivity of 100% (10 of 10 patients; 95% CI: 69%, 100%), specificity of 100% (seven of seven patients; 95% CI: 59%, 100%), and accuracy of 100% (17 of 17 patients; 95% CI: 80%, 100%). (111)In-capromab pendetide had a sensitivity of 10% (one of 10 patients; 95% CI: 0%, 45%), specificity of 100% (seven of seven patients; 95% CI: 59%, 100%), and accuracy of 47% (eight of 17 patients; 95% CI: 23%, 72%). CONCLUSION anti-3-(18)F-FACBC PET/CT was more sensitive than (111)In-capromab pendetide SPECT/CT in the detection of recurrent prostate carcinoma and is highly accurate in the differentiation of prostatic from extraprostatic disease. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11102023/-/DC1.
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Affiliation(s)
- David M Schuster
- Department of Radiology, Emory University Hospital, 1364 Clifton Rd, Atlanta, GA 30322, USA.
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Honer M, Mu L, Stellfeld T, Graham K, Martic M, Fischer CR, Lehmann L, Schubiger PA, Ametamey SM, Dinkelborg L, Srinivasan A, Borkowski S. 18F-labeled bombesin analog for specific and effective targeting of prostate tumors expressing gastrin-releasing peptide receptors. J Nucl Med 2011; 52:270-8. [PMID: 21233180 DOI: 10.2967/jnumed.110.081620] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
UNLABELLED Bombesin is a peptide exhibiting high affinity for the gastrin-releasing peptide receptor (GRPr), which is highly overexpressed on prostate cancer cells. In the present study, we developed an (18)F-labeled bombesin analog, (18)F-BAY 86-4367, which is currently being clinically tested for use in PET of prostate cancer. METHODS In vitro pharmacologic studies were performed to characterize the nonradioactive ((19)F) standard of the bombesin analog for binding affinity and selectivity for GRPr. The stability of (18)F-BAY 86-4367 was determined in murine and human plasma. In vivo, the tumor-targeting potential and pharmacokinetic profile of the (18)F tracer were analyzed with biodistribution experiments and PET studies of prostate tumor-bearing mice. RESULTS The nonradioactive ((19)F) standard of the bombesin analog showed subnanomolar and GRPr-selective binding affinity. The stability of the tracer in murine and human plasma was found to be high. In 2 prostate cancer xenograft models (PC-3 and LNCaP), (18)F-BAY 86-4367 showed more specific and effective GRPr-based targeting in vivo than the benchmark radiotracers (18)F-fluoroethylcholine and (18)F-FDG. In addition, rapid tumor targeting and fast renal excretion (∼70%) and hepatobiliary excretion (∼10%) were identified in both xenograft models. Furthermore, PET studies provided clear and specific visualization of PC-3 tumors in mice. CONCLUSION Favorable preclinical data showing specific and effective tumor targeting by (18)F-BAY 86-4367 suggest that a clinical trial be undertaken to test its diagnostic utility in PET for prostate carcinoma patients.
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Affiliation(s)
- Michael Honer
- Department of Chemistry and Applied Biosciences, Center for Radiopharmaceutical Sciences of ETH, PSI, and USZ, Zurich, Switzerland
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Dafni H, Larson PEZ, Hu S, Yoshihara HAI, Ward CS, Venkatesh HS, Wang C, Zhang X, Vigneron DB, Ronen SM. Hyperpolarized 13C spectroscopic imaging informs on hypoxia-inducible factor-1 and myc activity downstream of platelet-derived growth factor receptor. Cancer Res 2010; 70:7400-10. [PMID: 20858719 DOI: 10.1158/0008-5472.can-10-0883] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The recent development of hyperpolarized (13)C magnetic resonance spectroscopic imaging provides a novel method for in vivo metabolic imaging with potential applications for detection of cancer and response to treatment. Chemotherapy-induced apoptosis was shown to decrease the flux of hyperpolarized (13)C label from pyruvate to lactate due to depletion of NADH, the coenzyme of lactate dehydrogenase. In contrast, we show here that in PC-3MM2 tumors, inhibition of platelet-derived growth factor receptor with imatinib reduces the conversion of hyperpolarized pyruvate to lactate by lowering the expression of lactate dehydrogenase itself. This was accompanied by reduced expression of vascular endothelial growth factor and glutaminase, and is likely mediated by reduced expression of their transcriptional factors hypoxia-inducible factor-1 and c-Myc. Our results indicate that hyperpolarized (13)C MRSI could potentially detect the molecular effect of various cell signaling inhibitors, thus providing a radiation-free method to predict tumor response.
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Affiliation(s)
- Hagit Dafni
- Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California 94158, USA.
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Chen K, Conti PS. Target-specific delivery of peptide-based probes for PET imaging. Adv Drug Deliv Rev 2010; 62:1005-22. [PMID: 20851156 DOI: 10.1016/j.addr.2010.09.004] [Citation(s) in RCA: 126] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2010] [Revised: 09/08/2010] [Accepted: 09/08/2010] [Indexed: 12/19/2022]
Abstract
Positron emission tomography (PET) is one of the most rapidly growing areas of medical imaging, with many applications in the clinical management of patients with various diseases. The principal goal of PET imaging is to visualize, characterize, and measure biological processes at the cellular, subcellular, and molecular level in living subjects with non-invasive procedures. PET imaging takes advantage of the traditional diagnostic imaging techniques and introduces positron-emitting probes to determine the expression of indicative molecular targets at different stages of disease. During the last decade, advances in molecular biology have revealed an increasing number of potential molecular targets, including peptide receptors and peptide-related biomolecules. With the help of sophisticated bioconjugation and radiolabeling techniques, numerous peptide-based agents have been developed and evaluated for delivery of PET radionuclides to the specific molecular targets in preclinical and clinical studies. As compared to macromolecules, such as proteins or antibodies, low-molecular-weight peptides have their distinctive advantages and predominantly demonstrate their favorable pharmacokinetics for in vivo PET applications. This review summarizes the criteria of peptide-based PET probes design, the selection of radioisotopes, labeling methods, and provides an overview of the current status and trends in the development of target-specific peptide-based probes with respect to their unique PET imaging applications.
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