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Gallium Maltolate Disrupts Tumor Iron Metabolism and Retards the Growth of Glioblastoma by Inhibiting Mitochondrial Function and Ribonucleotide Reductase.
Chitambar CR, Al-Gizawiy MM, Alhajala HS, Pechman KR, Wereley JP, Wujek R, Clark PA, Kuo JS, Antholine WE, Schmainda KM
(2018) Mol Cancer Ther 17: 1240-1250
MeSH Terms: Animals, Antineoplastic Agents, Brain, Cell Line, Tumor, Disease Models, Animal, Glioblastoma, Heterografts, Humans, Immunohistochemistry, Iron, Male, Mitochondria, Organometallic Compounds, Pyrones, Rats, Receptors, Transferrin, Ribonucleoside Diphosphate Reductase, Ribonucleotide Reductases
Show Abstract · Added March 6, 2020
Gallium, a metal with antineoplastic activity, binds transferrin (Tf) and enters tumor cells via Tf receptor1 (TfR1); it disrupts iron homeostasis leading to cell death. We hypothesized that TfR1 on brain microvascular endothelial cells (BMEC) would facilitate Tf-Ga transport into the brain enabling it to target TfR-bearing glioblastoma. We show that U-87 MG and D54 glioblastoma cell lines and multiple glioblastoma stem cell (GSC) lines express TfRs, and that their growth is inhibited by gallium maltolate (GaM) After 24 hours of incubation with GaM, cells displayed a loss of mitochondrial reserve capacity followed by a dose-dependent decrease in oxygen consumption and a decrease in the activity of the iron-dependent M2 subunit of ribonucleotide reductase (RRM2). IHC staining of rat and human tumor-bearing brains showed that glioblastoma, but not normal glial cells, expressed TfR1 and RRM2, and that glioblastoma expressed greater levels of H- and L-ferritin than normal brain. In an orthotopic U-87 MG glioblastoma xenograft rat model, GaM retarded the growth of brain tumors relative to untreated control ( = 0.0159) and reduced tumor mitotic figures ( = 0.045). Tumors in GaM-treated animals displayed an upregulation of TfR1 expression relative to control animals, thus indicating that gallium produced tumor iron deprivation. GaM also inhibited iron uptake and upregulated TfR1 expression in U-87 MG and D54 cells We conclude that GaM enters the brain via TfR1 on BMECs and targets iron metabolism in glioblastoma thus inhibiting tumor growth. Further development of novel gallium compounds for brain tumor treatment is warranted. .
©2018 American Association for Cancer Research.
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68Ga-DOTATATE PET/CT imaging of indeterminate pulmonary nodules and lung cancer.
Walker R, Deppen S, Smith G, Shi C, Lehman J, Clanton J, Moore B, Burns R, Grogan EL, Massion PP
(2017) PLoS One 12: e0171301
MeSH Terms: Adult, Aged, Biopsy, Carcinoma, Non-Small-Cell Lung, Diagnosis, Differential, Female, Humans, Lung Neoplasms, Male, Middle Aged, Multimodal Imaging, Multiple Pulmonary Nodules, Neoplasm Metastasis, Organometallic Compounds, Positron Emission Tomography Computed Tomography
Show Abstract · Added January 29, 2018
PURPOSE - 18F-FDG PET/CT is widely used to evaluate indeterminate pulmonary nodules (IPNs). False positive results occur, especially from active granulomatous nodules. A PET-based imaging agent with superior specificity to 18F-FDG for IPNs, is badly needed, especially in areas of endemic granulomatous nodules. Somatostatin receptors (SSTR) are expressed in many malignant cells including small cell and non-small cell lung cancers (NSCLCs). 68Ga-DOTATATE, a positron emitter labeled somatostatin analog, combined with PET/CT imaging, may improve the diagnosis of IPNs over 18F-FDG by reducing false positives. Our study purpose was to test this hypothesis in our region with high endemic granulomatous IPNs.
METHODS - We prospectively performed 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT scans in the same 30 patients with newly diagnosed, treatment-naïve lung cancer (N = 14) or IPNs (N = 15) and one metastatic nodule. 68Ga-DOTATATE SUVmax levels at or above 1.5 were considered likely malignant. We analyzed the scan results, correlating with ultimate diagnosis via biopsy or 2-year chest CT follow-up. We also correlated 68Ga-DOTATATE uptake with immunohistochemical (IHC) staining for SSTR subtype 2A (SSTR2A) in pathological specimens.
RESULTS - We analyzed 31 lesions in 30 individuals, with 14 (45%) being non-neuroendocrine lung cancers and 1 (3%) being metastatic disease. McNemar's result comparing the two radiopharmaceuticals (p = 0.65) indicates that their accuracy of diagnosis in this indication are equivalent. 68Ga-DOTATATE was more specific (94% compared to 81%) and less sensitive 73% compared to 93%) than 18F-FDG. 68Ga-DOTATATE uptake correlated with SSTR2A expression in tumor stroma determined by immunohistochemical (IHC) staining in 5 of 9 (55%) NSCLCs.
CONCLUSION - 68Ga-DOTATATE and 18F-FDG PET/CT had equivalent accuracy in the diagnosis of non-neuroendocrine lung cancer and 68Ga-DOTATATE was more specific than 18F-FDG for the diagnosis of IPNs. IHC staining for SSTR2A receptor expression correlated with tumor stroma but not tumor cells.
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15 MeSH Terms
Safety and Efficacy of 68Ga-DOTATATE PET/CT for Diagnosis, Staging, and Treatment Management of Neuroendocrine Tumors.
Deppen SA, Liu E, Blume JD, Clanton J, Shi C, Jones-Jackson LB, Lakhani V, Baum RP, Berlin J, Smith GT, Graham M, Sandler MP, Delbeke D, Walker RC
(2016) J Nucl Med 57: 708-14
MeSH Terms: Female, Humans, Indium Radioisotopes, Intestinal Neoplasms, Lung Neoplasms, Male, Middle Aged, Neoplasm Staging, Neuroendocrine Tumors, Observer Variation, Organometallic Compounds, Pancreatic Neoplasms, Positron Emission Tomography Computed Tomography, Safety, Somatostatin, Stomach Neoplasms
Show Abstract · Added May 7, 2016
UNLABELLED - Our purpose was to evaluate the safety and efficacy of (68)Ga-DOTATATE PET/CT compared with (111)In-pentetreotide imaging for diagnosis, staging, and restaging of pulmonary and gastroenteropancreatic neuroendocrine tumors.
METHODS - (68)Ga-DOTATATE PET/CT and (111)In-pentetreotide scans were obtained for 78 of 97 consecutively enrolled patients with known or suspected pulmonary or gastroenteropancreatic neuroendocrine tumors. Safety and toxicity were measured by comparing vital signs, serum chemistry values, or acquisition-related medical complications before and after (68)Ga-DOTATATE injection. Added value was determined by changes in treatment plan when (68)Ga-DOTATATE PET/CT results were added to all prior imaging, including (111)In-pentetreotide. Interobserver reproducibility of (68)Ga-DOTATATE PET/CT scan interpretation was measured between blinded and nonblinded interpreters.
RESULTS - (68)Ga-DOTATATE PET/CT and (111)In-pentetreotide scans were significantly different in impact on treatment (P < 0.001). (68)Ga-DOTATATE PET/CT combined with CT or liver MRI changed care in 28 of 78 (36%) patients. Interobserver agreement between blinded and nonblinded interpreters was high. No participant had a trial-related event requiring treatment. Mild, transient events were tachycardia in 1, alanine transaminase elevation in 1, and hyperglycemia in 2 participants. No clinically significant arrhythmias occurred. (68)Ga-DOTATATE PET/CT correctly identified 3 patients for peptide-receptor radiotherapy incorrectly classified by (111)In-pentetreotide.
CONCLUSION - (68)Ga-DOTATATE PET/CT was equivalent or superior to (111)In-pentetreotide imaging in all 78 patients. No adverse events requiring treatment were observed. (68)Ga-DOTATATE PET/CT changed treatment in 36% of participants. Given the lack of significant toxicity, lower radiation exposure, and improved accuracy compared with (111)In-pentetreotide, (68)Ga-DOTATATE imaging should be used instead of (111)In-pentetreotide imaging where available.
© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
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16 MeSH Terms
Phosphorescence monitoring of hypoxic microenvironment in solid-tumors to evaluate chemotherapeutic effects using the hypoxia-sensitive iridium (III) coordination compound.
Zeng Y, Liu Y, Shang J, Ma J, Wang R, Deng L, Guo Y, Zhong F, Bai M, Zhang S, Wu D
(2015) PLoS One 10: e0121293
MeSH Terms: Adenocarcinoma, Animals, Antineoplastic Agents, Biological Transport, Cell Hypoxia, Cell Line, Tumor, Cell Survival, Cisplatin, Colonic Neoplasms, Coordination Complexes, Iridium, Luminescent Agents, Luminescent Measurements, Mice, Optical Imaging, Organometallic Compounds, Treatment Outcome, Tumor Microenvironment
Show Abstract · Added April 2, 2019
OBJECTIVES - To utilize phosphorescence to monitor hypoxic microenvironment in solid-tumors and investigate cancer chemotherapeutic effects in vivo.
METHODS - A hypoxia-sensitive probe named BTP was used to monitor hypoxic microenvironment in solid-tumors. The low-dose metronomic treatment with cisplatin was used in anti-angiogenetic chemotherapeutic programs. The phosphorescence properties of BTP were detected by a spectrofluorometer. BTP cytotoxicity utilized cell necrosis and apoptosis, which were evaluated by trypan blue dye exclusion and Hoechst33342 plus propidium iodide assays. Tumor-bearing mouse models of colon adenocarcinoma were used for tumor imaging in vivo. Monitoring of the hypoxic microenvironment in tumors was performed with a Maestro 2 fluorescence imaging system. Tumor tissues in each group were harvested regularly and treated with pathological hematoxylin and eosin and immunohistochemical staining to confirm imaging results.
RESULTS - BTP did not feature obvious cytotoxicity for cells, and tumor growth in low-dose metronomic cisplatin treated mice was significantly inhibited by chemotherapy. Hypoxic levels significantly increased due to cisplatin, as proven by the expression level of related proteins. Phosphorescence intensity in the tumors of mice in the cisplatin group was stronger and showed higher contrast than that in tumors of saline treated mice.
CONCLUSIONS - We develop a useful phosphorescence method to evaluate the chemotherapeutic effects of cisplatin. The proposed method shows potential as a phosphorescence imaging approach for evaluating chemotherapeutic effects in vivo, especially anti-angiogenesis.
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Immobilization of Ag(i) into a metal-organic framework with -SO3H sites for highly selective olefin-paraffin separation at room temperature.
Chang G, Huang M, Su Y, Xing H, Su B, Zhang Z, Yang Q, Yang Y, Ren Q, Bao Z, Chen B
(2015) Chem Commun (Camb) 51: 2859-62
MeSH Terms: Adsorption, Alkenes, Models, Molecular, Molecular Conformation, Organometallic Compounds, Paraffin, Silver, Temperature
Show Abstract · Added January 20, 2015
Introduction of Ag(i) ions into a sulfonic acid functionalized MOF ((Cr)-MIL-101-SO3H) significantly enhances its interactions with olefin double bonds, leading to its much higher selectivities for the separation of C2H4-C2H6 and C3H6-C3H8 at room temperature over the original (Cr)-MIL-101-SO3H and other adsorbents at room temperature.
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8 MeSH Terms
Cardiac epithelial-mesenchymal transition is blocked by monomethylarsonous acid (III).
Huang T, Barnett JV, Camenisch TD
(2014) Toxicol Sci 142: 225-38
MeSH Terms: Animals, Arsenites, Cell Culture Techniques, Cell Line, Cell Survival, Coronary Vessels, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Developmental, Mice, Transgenic, Organogenesis, Organometallic Compounds, Pericardium, Stem Cells
Show Abstract · Added February 21, 2016
Arsenic exposure during embryonic development can cause ischemic heart pathologies later in adulthood which may originate from impairment in proper blood vessel formation. The arsenic-associated detrimental effects are mediated by arsenite (iAs(III)) and its most toxic metabolite, monomethylarsonous acid [MMA (III)]. The impact of MMA (III) on coronary artery development has not yet been studied. The key cellular process that regulates coronary vessel development is the epithelial-mesenchymal transition (EMT). During cardiac EMT, activated epicardial progenitor cells transform to mesenchymal cells to form the cellular components of coronary vessels. Smad2/3 mediated TGFβ2 signaling, the key regulator of cardiac EMT, is disrupted by arsenite exposure. In this study, we compared the cardiac toxicity of MMA (III) with arsenite. Epicardial progenitor cells are 15 times more sensitive to MMA (III) cytotoxicity when compared with arsenite. MMA (III) caused a significant blockage in epicardial cellular transformation and invasion at doses 10 times lower than arsenite. Key EMT genes including TGFβ ligands, TβRIII, Has2, CD44, Snail1, TBX18, and MMP2 were down regulated by MMA (III) exposure. MMA (III) disrupted Smad2/3 activation at a dose 20 times lower than arsenite. Both arsenite and MMA (III) significantly inhibited Erk1/2 and Erk5 phosphorylation. Nuclear translocation of Smad2/3 and Erk5 was also blocked by arsenical exposure. However, p38 activation, as well as smooth muscle differentiation, was refractory to the inhibition by the arsenicals. Collectively, these findings revealed that MMA (III) is a selective disruptor of cardiac EMT and as such may predispose to arsenic-associated cardiovascular disorders.
© The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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13 MeSH Terms
Measured human dosimetry of 68Ga-DOTATATE.
Walker RC, Smith GT, Liu E, Moore B, Clanton J, Stabin M
(2013) J Nucl Med 54: 855-60
MeSH Terms: Humans, Lung Neoplasms, Male, Organometallic Compounds, Radiometry
Show Abstract · Added March 7, 2014
UNLABELLED - Measured human dosimetry of the (68)Ga-labeled synthetic somatostatin analog (68)Ga-DOTATATE has not been reported in the peer-reviewed literature. (68)Ga-DOTATATE is an investigational PET/CT imaging agent that binds with high affinity to somatostatin receptor subtype 2, found on many human cancers, most classically neuroendocrine tumors but also others. Reporting of measured dosimetry of (68)Ga-DOTATATE could be useful for investigations for diagnosis, staging, and restaging of somatostatin receptor-expressing tumors.
METHODS - We performed measured dosimetry with (68)Ga-DOTATATE PET/CT scanning in 6 volunteer human subjects as part of an Institutional Review Board-approved biodistribution investigation of the use of this radiopharmaceutical for possible future use in the diagnosis of indeterminate lung nodules or lung cancer. Five subjects were imaged at 3 time points, and 1 subject was imaged at 2 time points. Dosimetry was then measured for the whole body and for specific organs.
RESULTS - There were no observed adverse events to the radiopharmaceutical in the immediate or delayed time frames, with a follow-up of 1 y. One patient had stage IV non-small cell lung cancer and remains alive but with disease progressing on treatment. For the other 5 patients, it was ultimately proven that they had benign nodules. The measured dosimetry shows that the critical organ with (68)Ga-DOTATATE is the spleen, followed by the uroepithelium of the bladder, the kidneys, and the liver, in that order. Organ-specific and whole-body dosimetries for (68)Ga-DOTATATE were similar to but often slightly greater than those for (68)Ga-DOTATOC or (68)Ga-DOTANOC but less than those for (111)In-diethylenetriaminepentaacetic acid-octreotide.
CONCLUSION - No toxicity was observed in our 6 patients, and no adverse events occurred. The measured human dosimetry of (68)Ga-DOTATATE is similar to that of other (68)Ga-labeled somatostatin receptor analogs.
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5 MeSH Terms
A quantitative comparison of the influence of individual versus population-derived vascular input functions on dynamic contrast enhanced-MRI in small animals.
Loveless ME, Halliday J, Liess C, Xu L, Dortch RD, Whisenant J, Waterton JC, Gore JC, Yankeelov TE
(2012) Magn Reson Med 67: 226-36
MeSH Terms: Algorithms, Animals, Breast Neoplasms, Cell Line, Tumor, Contrast Media, Female, Gadolinium DTPA, Humans, Image Interpretation, Computer-Assisted, Magnetic Resonance Imaging, Mice, Mice, Inbred BALB C, Models, Biological, Organometallic Compounds, Reproducibility of Results, Sensitivity and Specificity
Show Abstract · Added November 13, 2013
For quantitative analysis of dynamic contrast enhanced magnetic resonance imaging data, the time course of the concentration of the contrast agent in the blood plasma, or vascular input function (VIF), is required. We compared pharmacokinetic parameters derived using individual and population-based VIFs in mice for two different contrast agents, gadopentetate dimeglumine and P846. Eleven mice with subcutaneous 4T(1) breast cancer xenografts were imaged at 7 T. A precontrast T(1) map was acquired along with dynamic T(1) -weighted gradient echo images before, during, and after a bolus injection of contrast agent delivered via a syringe pump. Each animal's individual VIF and derived population-averaged VIF were used to extract parameters from the signal-time curves of tumor tissue at both the region of interest and voxel level. The results indicate that for both contrast agents, K(trans) values estimated using population-averaged VIF have a high correlation (concordance correlation coefficient > 0.85) with K(trans) values estimated using individual VIF on both a region of interest and voxel level. This work supports the validity of using of a population-based VIF with a stringent injection protocol in preclinical dynamic contrast enhanced magnetic resonance imaging studies.
Copyright © 2011 Wiley-Liss, Inc.
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16 MeSH Terms
NADPH oxidases and reactive oxygen species at different stages of chronic hypoxia-induced pulmonary hypertension in newborn piglets.
Dennis KE, Aschner JL, Milatovic D, Schmidt JW, Aschner M, Kaplowitz MR, Zhang Y, Fike CD
(2009) Am J Physiol Lung Cell Mol Physiol 297: L596-607
MeSH Terms: Animals, Animals, Newborn, Antioxidants, Catalase, F2-Isoprostanes, Hypertension, Pulmonary, Hypoxia, Immunoblotting, Luminescence, Manganese, NADPH Oxidase 1, NADPH Oxidases, Organometallic Compounds, Phosphoproteins, Pulmonary Artery, Reactive Oxygen Species, Superoxide Dismutase, Superoxide Dismutase-1, Swine, Vascular Resistance
Show Abstract · Added April 7, 2010
Recently, we reported that reactive oxygen species (ROS) generated by NADPH oxidase (NOX) contribute to aberrant responses in pulmonary resistance arteries (PRAs) of piglets exposed to 3 days of hypoxia (Am J Physiol Lung Cell Mol Physiol 295: L881-L888, 2008). An objective of the present study was to determine whether NOX-derived ROS also contribute to altered PRA responses at a more advanced stage of pulmonary hypertension, after 10 days of hypoxia. We further wished to advance knowledge about the specific NOX and antioxidant enzymes that are altered at early and later stages of pulmonary hypertension. Piglets were raised in room air (control) or hypoxia for 3 or 10 days. Using a cannulated artery technique, we found that treatments with agents that inhibit NOX (apocynin) or remove ROS [an SOD mimetic (M40403) + polyethylene glycol-catalase] diminished responses to ACh in PRAs from piglets exposed to 10 days of hypoxia. Western blot analysis showed an increase in expression of NOX1 and the membrane fraction of p67phox. Expression of NOX4, SOD2, and catalase were unchanged, whereas expression of SOD1 was reduced, in arteries from piglets raised in hypoxia for 3 or 10 days. Markers of oxidant stress, F(2)-isoprostanes, measured by gas chromatography-mass spectrometry, were increased in PRAs from piglets raised in hypoxia for 3 days, but not 10 days. We conclude that ROS derived from some, but not all, NOX family members, as well as alterations in the antioxidant enzyme SOD1, contribute to aberrant PRA responses at an early and a more progressive stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets.
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20 MeSH Terms
Room-temperature Pd-catalyzed amidation of aryl bromides using tert-butyl carbamate.
Bhagwanth S, Waterson AG, Adjabeng GM, Hornberger KR
(2009) J Org Chem 74: 4634-7
MeSH Terms: Aniline Compounds, Bromobenzenes, Carbamates, Catalysis, Organometallic Compounds, Palladium, Temperature
Show Abstract · Added March 5, 2014
The scope of Pd-catalyzed synthesis of N-Boc-protected anilines from aryl bromides and commercially available tert-butyl carbamate is described. For the first time, this process can be conducted at room temperature (17-22 degrees C) using a combination of Pd(2)dba(3).CHCl(3) and a monodentate ligand, tert-butyl X-Phos. Use of sodium tert-butoxide is crucial to the success of the reaction, which proceeds in 43-83% yield.
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7 MeSH Terms