MRI of the tumor microenvironment

Gillies, Robert J.; Raghunand, Natarajan; Karczmar, Gregory S.; Bhujwalla, Zaver M.

doi:10.1002/jmri.10181

Cited by 502 publications

(424 citation statements)

References 181 publications

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“…An excellent review by Gillies et al was recently published about the NMR view on the tumor microenvironment. 87 The indirect detection of oxygen by NMR can be performed by observing the effect of the paramagnetism of oxygen on NMR signals and the alteration of the relaxation times. 88 The effect of oxygen on NMR relation times is ubiquitous, but for tumor applications, 1 H and 19 F have mainly been used.…”

Section: Techniques For the Assessment Of Tumor Oxygenationmentioning

confidence: 99%

Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications

2004

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This review paper attempts to provide an overview of the principles and techniques that are often termed electron paramagnetic resonance (EPR) oximetry. The paper discusses the potential of such methods and illustrates they have been successfully applied to measure oxygen tension, an essential parameter of the tumor microenvironment. To help the reader understand the motivation for carrying out these measurements, the importance of tumor hypoxia is first discussed: the basic issues of why a tumor is hypoxic, why these hypoxic microenvironments promote processes driving malignant progression and why hypoxia dramatically influences the response of tumors to cytotoxic treatments will be explained. The different methods that have been used to estimate the oxygenation in tumors will be reviewed. To introduce the basics of EPR oximetry, the specificity of in vivo EPR will be discussed by comparing this technique with NMR and MRI. The different types of paramagnetic oxygen sensors will be presented, as well as the methods for recording the information (EPR spectroscopy, EPR imaging, dynamic nuclear polarization). Several applications of EPR for characterizing tumor oxygenation will be illustrated, with a special emphasis on pharmacological interventions that modulate the tumor microenvironment. Finally, the challenges for transposing the method into the clinic will also be discussed.

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Section: Techniques For the Assessment Of Tumor Oxygenationmentioning

confidence: 99%

Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications

2004

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“…It allows non invasive characterization of phosphate containing compounds within tumour cells and determination of energy status and pH [9][10][11]. It basically reflects three fundamental processes of the cell; like bioenergetics, cell membrane phospholipid turnover and intracellular pH.…”

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confidence: 99%

Energy Status And Metabolism in Intracranial Space Occupying Lesions: A Prospective 31p Spectroscopic Study

Kamble¹

2014

JCDR

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Aim: Intracranial space occupying lesions can be infective or tumour. There are various advanced Magnetic resonance imaging techniques like perfusion, diffusion and proton spectroscopy which can differentiate between them. However, 31 Phosphorus spectroscopy studies the energy status and the metabolism pattern of various tissues and can be used potentially to differentiate between them depending on their Metabolism pattern. Thus, we aimed to study energy status of various intracranial lesions and try to differentiate between them including grades of gliomas. Materials and Methods:31 PMRS was done in 1.5T MRI in 43 patients prior to surgery or through/via stereo-tactic biopsy, of which 25 were men and 18 women with mean age 41.34 y ranging from 7-71 y. Single voxel phosphorus spectroscopy was done from the solid portion of the lesions and data was analysed and post processed.Results: Study includes Lymphoma (n=6), Grade 1 and 2 glioma (n=5), grade 3 glioma (n=9), grade 4 glioma(n=6), metastases (n=5), tuberculoma (n=7) and pyogenic abscesses (n=5). The integral values of PME, Pi, PDE, γ-ATP, α-ATP, β-ATP with reference to the position of PCr were calculated along with various ratios. Integral values of Pi and PDE were significantly increased in metastases but decreased in gliomas grade 1-2 compared to other pathologic conditions. Mean integral values of LEP (low energy phosphates) and total phosphates were significantly decreased in gliomas grades 1 and 2 and increased in metastases when compared with other pathologic conditions. PCr /Pi was increased in glioma grades 1, 2 and 3 but decreased in metastases; the significance was observed only in gliomas grade 3 and metastases. Metabolic ratios of PDE/βATP and Pi/ βATP were decreased in glioma grades 1 and 2 and increased in metastases with statistical significance. Conclusion:31 PMRS may help in differentiating primary from secondary lesions and assess grades of gliomas. P MR spectroscopy (TR = 400ms, TE=1ms, 512 acquisitions) using intravoxel in-vivo spectroscopy localization method with head quadrature dual-tuned coil. Care was taken to include mainly the solid portion of the lesion in the MRS voxel which ranged from 2 cm 3 -4 cm 3 . The duration of spectroscopy examination was about 5 min. Spectroscopy data were transferred to an installed software programme (Numaris spectroscopy analysis package VB33A). All post-processing techniques like apodization, zero and first order phase corrections were performed and spectra were plotted, analyzed and fitted to Lorentzian lines shapes.The following well resolved phosphorus metabolite peaks were observed in all patients-Phosphomonoesters (PME), Inorganic phosphate (Pi), Phosphodiesters (PDE), Phosphocreatine (PCr), γ, β, and α resonances of adenosine triphosphate (ATP). The chemical

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“…Considering the fact that the extracellular pH in tumors is more acidic than in normal tissues, (41) and assuming that the endothelial cells of vessels in tumors are under the influence of the acidic extracellular tumor pH, one may reason that the pH profile of the fumagillin-MetAP binding reaction leads to selectivity (or targeting) of the fumagillin effect to tumor vessels.…”

Section: Discussionmentioning

confidence: 99%

Protonation States of Methionine Aminopeptidase and Their Relevance for Inhibitor Binding and Catalytic Activity

Klein

Schiffmann

Folkers³

et al. 2003

Journal of Biological Chemistry

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We have performed a computational study of different protomeric states of the methionine aminopeptidase active site using a combined quantum-mechanical/molecular mechanical simulation approach. The aim of this study was to clarify the native protonation state of the enzyme, which is needed for the development of novel irreversible inhibitors that can possibly be used as antiangiogenic and antibiotic drugs by virtual screening and other drug design methods. The results of the simulations indicated that two protonation states are possible without disturbing the overall geometry of the active site. We then verified experimentally the presence of the two protonation states by studying the substrate hydrolysis and inhibitor binding reactions at different pH values and come to the conclusion that one of the protomeric states is relevant for inhibitor binding, whereas the other is relevant for substrate hydrolysis. This result has implications for the development of other inhibitors of this class of enzymes and adds a new perspective to the pharmacological properties of the antiangiogenic drug fumagillin, which is an irreversible inhibitor of the human methionine aminopeptidase type II.Methionine aminopeptidases (MetAPs) 1 play a central role for in vivo protein synthesis as they remove the starter methionine from newly synthetized proteins. The natural product fumagillin, an epoxide, covalently modifies one of the activesite histidines in the eukaryotic methionine aminopeptidase II (MetAP-II) (1-4) and other MetAPs (cf. Fig. 1). Fumagillin inhibits the growth of vessels in tumors, and a derivative of the compound has been evaluated in clinical trials as an anticancer drug. The antiangiogenic effect of fumagillin and other inhibitors of MetAP-II have been attributed to the inhibition of the Ets-1 transcription factor expression and the activation of the p53 pathway (5, 6). Besides from being anticancer drug targets, MetAPs have the potential to become the target proteins of antibacterial substances because the MetAP functionality is essential for cell growth and bacteria possess only one of the two known MetAP subtypes (7).MetAPs are metal-dependent enzymes. It is not clear which metal activates the MetAPs in vivo. For in vitro experiments, cobalt is commonly used because it activates all known MetAPs and the cobalt-substituted enzymes are usually the most active (8). Zinc and iron(II) have also been shown to activate some MetAPs (9, 10). The metal-chelating residues in all known MetAPs are two glutamates, two aspartates, and one histidine. The geometric arrangement of these residues is practically identical in all of the MetAP x-ray structures (11,12). Several three-dimensional structures of MetAPs have been determined by x-ray diffraction methods including the structure of human MetAP-II with a covalently bound fumagillin molecule (13-15).Density functional theory (16, 17) has long been used to study the reactivity of organic molecules and recently began to find its way into biochemistry (18). We present here an ex...

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MRI of the tumor microenvironment

Cited by 502 publications

References 181 publications

Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications

Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications

Energy Status And Metabolism in Intracranial Space Occupying Lesions: A Prospective 31p Spectroscopic Study

Protonation States of Methionine Aminopeptidase and Their Relevance for Inhibitor Binding and Catalytic Activity

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