John Griffiths | University of Cambridge (original) (raw)

Papers by John Griffiths

Research paper thumbnail of HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells

Cells, 2021

In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adapta... more In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in ...

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Research paper thumbnail of How and Why Are Cancers Acidic? Carbonic Anhydrase IX and the Homeostatic Control of Tumour Extracellular pH

Cancers, 2020

The acidic tumour microenvironment is now recognized as a tumour phenotype that drives cancer som... more The acidic tumour microenvironment is now recognized as a tumour phenotype that drives cancer somatic evolution and disease progression, causing cancer cells to become more invasive and to metastasise. This property of solid tumours reflects a complex interplay between cellular carbon metabolism and acid removal that is mediated by cell membrane carbonic anhydrases and various transport proteins, interstitial fluid buffering, and abnormal tumour-associated vessels. In the past two decades, a convergence of advances in the experimental and mathematical modelling of human cancers, as well as non-invasive pH-imaging techniques, has yielded new insights into the physiological mechanisms that govern tumour extracellular pH (pHe). In this review, we examine the mechanisms by which solid tumours maintain a low pHe, with a focus on carbonic anhydrase IX (CAIX), a cancer-associated cell surface enzyme. We also review the accumulating evidence that suggest a role for CAIX as a biological pH-s...

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Research paper thumbnail of Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo

British journal of cancer, Jan 12, 2018

Tumour carbonic anhydrase IX (CAIX), a hypoxia-inducible tumour-associated cell surface enzyme, i... more Tumour carbonic anhydrase IX (CAIX), a hypoxia-inducible tumour-associated cell surface enzyme, is thought to acidify the tumour microenvironment by hydrating CO to form protons and bicarbonate, but there is no definitive evidence for this in solid tumours in vivo. We used H magnetic resonance spectroscopic imaging (MRSI) of the extracellular pH probe imidazolyl succinic acid (ISUCA) to measure and spatially map extracellular pH in HCT116 tumours transfected to express CAIX and empty vector controls in SCID mice. We also measured intracellular pH in situ with P MRS and measured lactate in freeze-clamped tumours. CAIX-expressing tumours had 0.15 pH-unit lower median extracellular pH than control tumours (pH 6.71 tumour vs pH 6.86 control, P = 0.01). Importantly, CAIX expression imposed an upper limit for tumour extracellular pH at 6.93. Despite the increased lactate concentration in CAIX-expressing tumours, P MRS showed no difference in intracellular pH, suggesting that CAIX acidifie...

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Research paper thumbnail of Supplementary Table 4

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Research paper thumbnail of Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo

British journal of cancer, Jan 15, 2014

The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcino... more The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcinoma (PDAC) are well documented, with drug delivery and metabolic lability cited as important contributing factors. We have used a mouse model of PDAC: KRAS(G12D); p53(R172H); pdx-Cre (KPC) that recapitulates the human disease to study dFdC intra-tumoural metabolism. LC-MS/MS and NMR were used to measure drug and physiological analytes. Cytotoxicity was assessed by the Sulphorhodamine B assay. In KPC tumour tissue, we identified a new, Kennedy pathway-linked dFdC metabolite (gemcitabine diphosphate choline (GdPC)) present at equimolar amounts to its precursor, the accepted active metabolite gemcitabine triphosphate (dFdCTP). Utilising additional subcutaneous PDAC tumour models, we demonstrated an inverse correlation between GdPC/dFdCTP ratios and cytidine triphosphate (CTP). In tumour homogenates in vitro, CTP inhibited GdPC formation from dFdCTP, indicating competition between CTP and dFd...

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Research paper thumbnail of Development of NMR: Biological and Medical MR Spectroscopy

Encyclopedia of Magnetic Resonance, 2012

Localized magnetic resonance spectroscopy has seen substantial developments over the past two dec... more Localized magnetic resonance spectroscopy has seen substantial developments over the past two decades. It has been able to take advantage of the great improvements in hardware, including the shift to higher magnetic fields, faster and stronger magnetic field gradients with better shielding, parallel RF receive and transmit technology, and improved RF detection sensitivity. Acquisition methods have benefited from more flexible RF and gradient pulse shapes, more rapid sampling of k-space for spectroscopic imaging, and efficient automated shimming algorithms. Spectral processing and quantification have seen the development of fitting packages such as java magnetic resonance user interface (jMRUI) and LCModel. Applications have tended to focus mostly on the 1H nucleus, being the most abundant and sensitive. However, studies using 19F and 31P continue, with the development of the dynamic nuclear polarization (DNP) method of hyperpolarization spawning a huge interest in 13C measurements of small molecules, in particular, [1-13C] pyruvate. Preclinical measurements benefit from the same technological advances. Exvivo measurement of tissue samples using high-resolution magic angle spinning permits subsequent histology to be performed on the same sample, and has become widely used for both preclinical and clinical studies. Keywords: magnetic resonance spectroscopy; history; in vivo; clinical; localization; metabolism; 1H

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Research paper thumbnail of Visualisation of Multidimensional Data for Medical Decision Support

Lecture Notes in Computer Science, 2001

Medical decision support tools are not widely used by clinicians, perhaps because most do not exp... more Medical decision support tools are not widely used by clinicians, perhaps because most do not explain the decisions. We describe an approach for case-based systems using automated pattern recognition techniques. Multivariate methods estimate the degree of similarity between a new case and those in the database, and graphical displays allow users to combine this information with their own expertise. The approach is demonstrated by an example, the SpectraVisualizer, which allows radiologists to interpret magnetic ...

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Research paper thumbnail of Intersample fluctuations in phosphocreatine concentration determined by 31P‐magnetic resonance spectroscopy and parameter estimation of metabolic responses to exercise in humans

The Journal of Physiology, 2000

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Research paper thumbnail of The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis

The EMBO Journal, 2011

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Research paper thumbnail of Towards a method for automated classification of1H MRS spectra from brain tumours

NMR in Biomedicine, 1998

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Research paper thumbnail of Pharmacokinetics of the 13C labeled anticancer agent temozolomide detected in vivo by selective cross‐polarization transfer

Magnetic Resonance in Medicine, 1995

The anticancer agent temozolomide labeled with 13C (8‐Carbamoyl‐3‐13C‐methylimidazo‐[5,1‐d]‐1,2,3... more The anticancer agent temozolomide labeled with 13C (8‐Carbamoyl‐3‐13C‐methylimidazo‐[5,1‐d]‐1,2,3,5‐tetrazin‐4‐(3H)‐one), was noninvasively detected in subcutaneous RIF‐1 tumors by a selective cross polarization 13C NMR method, at a field strength of 9.4T. Pharmacokinetics of the drug, at a dose of 150 mg/kg, were determined for intravenous and intraperitoneal modes of administration (three animals per mode). The half‐life of the drug in the tumors was approximately 60 min. The uptake and clearance of the drug, however, varied significantly between individual hosts, for both modes of administration. These results demonstrate the feasibility of obtaining pharmacokinetics of anticancer agents for individual tumors without the need for a label that might modify drug activity (e.g., fluorine). The variability of the in vivo measurements, even within the same tumor model, demonstrates the necessity of directly monitoring the tumor to evaluate drug pharmacokinetics.

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Research paper thumbnail of Independent component analysis for automated decomposition of in vivo magnetic resonance spectra

Magnetic Resonance in Medicine, 2003

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Research paper thumbnail of Effect of Gd-DTPA-BMA on choline signals of HT29 tumors detected by in vivo 1 H MRS

Journal of Magnetic Resonance Imaging, 2008

To study the impact of Gd-DTPA-BMA on choline signals of HT29 colon carcinomas determined by loca... more To study the impact of Gd-DTPA-BMA on choline signals of HT29 colon carcinomas determined by localized 1H MRS in vivo at 4.7T. PRESS 1H MR spectra (2-second repetition time and echo times of 20-272 msec) were acquired from HT29 xenografts prior to and following intravenous administration of 0.1 or 0.2 mmol/kg Gd-DTPA-BMA. The magnetic resonance spectroscopy (MRS) data were analyzed by 1) normalizing choline and water peak areas to their precontrast values; and 2) estimating absolute choline concentration relative to tissue water. Changes in the T1 and T2 of choline and water were apparent following administration of Gd-DTPA-BMA. Administration of 0.1 mmol/kg Gd-DTPA-BMA induced significant increases in the choline peak area, concomitant with enhancements of the water peak area, whereas 0.2 mmol/kg Gd-DTPA-BMA induced no enhancement of choline peak area but significant increases in water peak area at short echo times. The effect of Gd-DTPA-BMA on estimation of tumor choline concentration varied with the dose of contrast agent, the echo time, and the time after contrast agent administration. These data highlight the potential pitfalls associated with the modulation of choline and water signals post-Gd-DTPA-BMA and may account for the apparently contradictory results previously reported.

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Research paper thumbnail of Assessment of antiangiogenic and antivascular therapeutics using MRI: recommendations for appropriate methodology for clinical trials

The British Journal of Radiology, 2003

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Research paper thumbnail of Histone Deacetylase Inhibition Increases Levels of Choline Kinase α and Phosphocholine Facilitating Noninvasive Imaging in Human Cancers

Cancer Research, 2011

Histone deacetylase (HDAC) inhibitors are currently approved for cutaneous T-cell lymphoma and ar... more Histone deacetylase (HDAC) inhibitors are currently approved for cutaneous T-cell lymphoma and are in mid-late stage trials for other cancers. The HDAC inhibitors LAQ824 and SAHA increase phosphocholine (PC) levels in human colon cancer cells and tumor xenografts as observed by magnetic resonance spectroscopy (MRS). In this study, we show that belinostat, an HDAC inhibitor with an alternative chemical scaffold, also caused a rise in cellular PC content that was detectable by 1H and 31P MRS in prostate and colon carcinoma cells. In addition, 1H MRS showed an increase in branched chain amino acid and alanine concentrations. 13C-choline labeling indicated that the rise in PC resulted from increased de novo synthesis and correlated with an induction of choline kinase α expression. Furthermore, metabolic labeling experiments with 13C-glucose showed that differential glucose routing favored alanine formation at the expense of lactate production. Additional analysis revealed increases in t...

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Research paper thumbnail of Effects of fructose on the energy metabolism and acid-base status of the perfused starved-rat liver. A 31 phosphorus nuclear magnetic resonance study

Biochemical Journal, 1980

Fructose metabolism has been studied with 31P n.m.r. in perfused livers from rats starved for 48h... more Fructose metabolism has been studied with 31P n.m.r. in perfused livers from rats starved for 48h. The time course of changes in liver ATP, Pi and sugar phosphate (fructose l-phosphate) concentrations, and intracellular pH were followed in each perfusion after infusion of fructose to give an initial concentration of either 5mM or 10mM. Rapid falls in the concentrations of ATP and Pi and intracellular pH occurred after infusion of fructose, reaching a minimum after 4-5 min, which was lower in the 10mM group than in the 5mM group. These changes were accompanied by a rapid rise in fructose 1-phosphate, reaching a plateau also after 4-5 min. At both concentrations of fructose, after the early falls, some recovery of ATP, Pi and intracellular pH occurred; this was complete for Pi and intracellular pH in the 5mM-fructose experiments (within 12-30 min). Complete restoration of ATP to the pre-fructose value was not achieved in either the 5mM of 10mM groups. Measurements of the uptake of lac...

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Research paper thumbnail of Are cancer cells acidic?

British Journal of Cancer, 1991

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Research paper thumbnail of Effect of Radiofrequency Transmit Field Correction on Quantitative Dynamic Contrast-enhanced MR Imaging of the Breast at 3.0 T

Radiology, Jan 16, 2015

Purpose To investigate the effects of radiofrequency transmit field (B1(+)) correction on (a) the... more Purpose To investigate the effects of radiofrequency transmit field (B1(+)) correction on (a) the measured T1 relaxation times of normal breast tissue and malignant lesions and (b) the pharmacokinetically derived parameters of malignant breast lesions at 3 T. Materials and Methods Ethics approval and informed consent were obtained. Between May 2013 and January 2014, 30 women (median age, 58 years; range, 32-83 years) with invasive ductal carcinoma of at least 10 mm were recruited to undergo dynamic contrast material-enhanced magnetic resonance (MR) imaging before surgery. B1(+) and T1 mapping sequences were performed to determine the effect of B1(+) correction on the native tissue relaxation time (T10) of fat, parenchyma, and malignant lesions in both breasts. Pharmacokinetic parameters were calculated before and after correction for B1(+) variations. Results were correlated with histologic grade by using the Kruskal-Wallis test. Results Measurements showed a mean 37% flip angle dif...

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Research paper thumbnail of The response to carbogen breathing in experimental tumour models monitored by gradient-recalled echo magnetic resonance imaging

British Journal of Cancer, 1997

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Research paper thumbnail of Growth studies of subcutaneous rat tumours: comparison of 31P-NMR spectroscopy, acid extracts and histology

British Journal of Cancer, 1989

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Research paper thumbnail of HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells

Cells, 2021

In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adapta... more In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in ...

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Research paper thumbnail of How and Why Are Cancers Acidic? Carbonic Anhydrase IX and the Homeostatic Control of Tumour Extracellular pH

Cancers, 2020

The acidic tumour microenvironment is now recognized as a tumour phenotype that drives cancer som... more The acidic tumour microenvironment is now recognized as a tumour phenotype that drives cancer somatic evolution and disease progression, causing cancer cells to become more invasive and to metastasise. This property of solid tumours reflects a complex interplay between cellular carbon metabolism and acid removal that is mediated by cell membrane carbonic anhydrases and various transport proteins, interstitial fluid buffering, and abnormal tumour-associated vessels. In the past two decades, a convergence of advances in the experimental and mathematical modelling of human cancers, as well as non-invasive pH-imaging techniques, has yielded new insights into the physiological mechanisms that govern tumour extracellular pH (pHe). In this review, we examine the mechanisms by which solid tumours maintain a low pHe, with a focus on carbonic anhydrase IX (CAIX), a cancer-associated cell surface enzyme. We also review the accumulating evidence that suggest a role for CAIX as a biological pH-s...

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Research paper thumbnail of Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo

British journal of cancer, Jan 12, 2018

Tumour carbonic anhydrase IX (CAIX), a hypoxia-inducible tumour-associated cell surface enzyme, i... more Tumour carbonic anhydrase IX (CAIX), a hypoxia-inducible tumour-associated cell surface enzyme, is thought to acidify the tumour microenvironment by hydrating CO to form protons and bicarbonate, but there is no definitive evidence for this in solid tumours in vivo. We used H magnetic resonance spectroscopic imaging (MRSI) of the extracellular pH probe imidazolyl succinic acid (ISUCA) to measure and spatially map extracellular pH in HCT116 tumours transfected to express CAIX and empty vector controls in SCID mice. We also measured intracellular pH in situ with P MRS and measured lactate in freeze-clamped tumours. CAIX-expressing tumours had 0.15 pH-unit lower median extracellular pH than control tumours (pH 6.71 tumour vs pH 6.86 control, P = 0.01). Importantly, CAIX expression imposed an upper limit for tumour extracellular pH at 6.93. Despite the increased lactate concentration in CAIX-expressing tumours, P MRS showed no difference in intracellular pH, suggesting that CAIX acidifie...

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Research paper thumbnail of Supplementary Table 4

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Research paper thumbnail of Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo

British journal of cancer, Jan 15, 2014

The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcino... more The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcinoma (PDAC) are well documented, with drug delivery and metabolic lability cited as important contributing factors. We have used a mouse model of PDAC: KRAS(G12D); p53(R172H); pdx-Cre (KPC) that recapitulates the human disease to study dFdC intra-tumoural metabolism. LC-MS/MS and NMR were used to measure drug and physiological analytes. Cytotoxicity was assessed by the Sulphorhodamine B assay. In KPC tumour tissue, we identified a new, Kennedy pathway-linked dFdC metabolite (gemcitabine diphosphate choline (GdPC)) present at equimolar amounts to its precursor, the accepted active metabolite gemcitabine triphosphate (dFdCTP). Utilising additional subcutaneous PDAC tumour models, we demonstrated an inverse correlation between GdPC/dFdCTP ratios and cytidine triphosphate (CTP). In tumour homogenates in vitro, CTP inhibited GdPC formation from dFdCTP, indicating competition between CTP and dFd...

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Research paper thumbnail of Development of NMR: Biological and Medical MR Spectroscopy

Encyclopedia of Magnetic Resonance, 2012

Localized magnetic resonance spectroscopy has seen substantial developments over the past two dec... more Localized magnetic resonance spectroscopy has seen substantial developments over the past two decades. It has been able to take advantage of the great improvements in hardware, including the shift to higher magnetic fields, faster and stronger magnetic field gradients with better shielding, parallel RF receive and transmit technology, and improved RF detection sensitivity. Acquisition methods have benefited from more flexible RF and gradient pulse shapes, more rapid sampling of k-space for spectroscopic imaging, and efficient automated shimming algorithms. Spectral processing and quantification have seen the development of fitting packages such as java magnetic resonance user interface (jMRUI) and LCModel. Applications have tended to focus mostly on the 1H nucleus, being the most abundant and sensitive. However, studies using 19F and 31P continue, with the development of the dynamic nuclear polarization (DNP) method of hyperpolarization spawning a huge interest in 13C measurements of small molecules, in particular, [1-13C] pyruvate. Preclinical measurements benefit from the same technological advances. Exvivo measurement of tissue samples using high-resolution magic angle spinning permits subsequent histology to be performed on the same sample, and has become widely used for both preclinical and clinical studies. Keywords: magnetic resonance spectroscopy; history; in vivo; clinical; localization; metabolism; 1H

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Research paper thumbnail of Visualisation of Multidimensional Data for Medical Decision Support

Lecture Notes in Computer Science, 2001

Medical decision support tools are not widely used by clinicians, perhaps because most do not exp... more Medical decision support tools are not widely used by clinicians, perhaps because most do not explain the decisions. We describe an approach for case-based systems using automated pattern recognition techniques. Multivariate methods estimate the degree of similarity between a new case and those in the database, and graphical displays allow users to combine this information with their own expertise. The approach is demonstrated by an example, the SpectraVisualizer, which allows radiologists to interpret magnetic ...

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Research paper thumbnail of Intersample fluctuations in phosphocreatine concentration determined by 31P‐magnetic resonance spectroscopy and parameter estimation of metabolic responses to exercise in humans

The Journal of Physiology, 2000

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Research paper thumbnail of The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis

The EMBO Journal, 2011

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Research paper thumbnail of Towards a method for automated classification of1H MRS spectra from brain tumours

NMR in Biomedicine, 1998

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Research paper thumbnail of Pharmacokinetics of the 13C labeled anticancer agent temozolomide detected in vivo by selective cross‐polarization transfer

Magnetic Resonance in Medicine, 1995

The anticancer agent temozolomide labeled with 13C (8‐Carbamoyl‐3‐13C‐methylimidazo‐[5,1‐d]‐1,2,3... more The anticancer agent temozolomide labeled with 13C (8‐Carbamoyl‐3‐13C‐methylimidazo‐[5,1‐d]‐1,2,3,5‐tetrazin‐4‐(3H)‐one), was noninvasively detected in subcutaneous RIF‐1 tumors by a selective cross polarization 13C NMR method, at a field strength of 9.4T. Pharmacokinetics of the drug, at a dose of 150 mg/kg, were determined for intravenous and intraperitoneal modes of administration (three animals per mode). The half‐life of the drug in the tumors was approximately 60 min. The uptake and clearance of the drug, however, varied significantly between individual hosts, for both modes of administration. These results demonstrate the feasibility of obtaining pharmacokinetics of anticancer agents for individual tumors without the need for a label that might modify drug activity (e.g., fluorine). The variability of the in vivo measurements, even within the same tumor model, demonstrates the necessity of directly monitoring the tumor to evaluate drug pharmacokinetics.

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Research paper thumbnail of Independent component analysis for automated decomposition of in vivo magnetic resonance spectra

Magnetic Resonance in Medicine, 2003

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Research paper thumbnail of Effect of Gd-DTPA-BMA on choline signals of HT29 tumors detected by in vivo 1 H MRS

Journal of Magnetic Resonance Imaging, 2008

To study the impact of Gd-DTPA-BMA on choline signals of HT29 colon carcinomas determined by loca... more To study the impact of Gd-DTPA-BMA on choline signals of HT29 colon carcinomas determined by localized 1H MRS in vivo at 4.7T. PRESS 1H MR spectra (2-second repetition time and echo times of 20-272 msec) were acquired from HT29 xenografts prior to and following intravenous administration of 0.1 or 0.2 mmol/kg Gd-DTPA-BMA. The magnetic resonance spectroscopy (MRS) data were analyzed by 1) normalizing choline and water peak areas to their precontrast values; and 2) estimating absolute choline concentration relative to tissue water. Changes in the T1 and T2 of choline and water were apparent following administration of Gd-DTPA-BMA. Administration of 0.1 mmol/kg Gd-DTPA-BMA induced significant increases in the choline peak area, concomitant with enhancements of the water peak area, whereas 0.2 mmol/kg Gd-DTPA-BMA induced no enhancement of choline peak area but significant increases in water peak area at short echo times. The effect of Gd-DTPA-BMA on estimation of tumor choline concentration varied with the dose of contrast agent, the echo time, and the time after contrast agent administration. These data highlight the potential pitfalls associated with the modulation of choline and water signals post-Gd-DTPA-BMA and may account for the apparently contradictory results previously reported.

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Research paper thumbnail of Assessment of antiangiogenic and antivascular therapeutics using MRI: recommendations for appropriate methodology for clinical trials

The British Journal of Radiology, 2003

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Research paper thumbnail of Histone Deacetylase Inhibition Increases Levels of Choline Kinase α and Phosphocholine Facilitating Noninvasive Imaging in Human Cancers

Cancer Research, 2011

Histone deacetylase (HDAC) inhibitors are currently approved for cutaneous T-cell lymphoma and ar... more Histone deacetylase (HDAC) inhibitors are currently approved for cutaneous T-cell lymphoma and are in mid-late stage trials for other cancers. The HDAC inhibitors LAQ824 and SAHA increase phosphocholine (PC) levels in human colon cancer cells and tumor xenografts as observed by magnetic resonance spectroscopy (MRS). In this study, we show that belinostat, an HDAC inhibitor with an alternative chemical scaffold, also caused a rise in cellular PC content that was detectable by 1H and 31P MRS in prostate and colon carcinoma cells. In addition, 1H MRS showed an increase in branched chain amino acid and alanine concentrations. 13C-choline labeling indicated that the rise in PC resulted from increased de novo synthesis and correlated with an induction of choline kinase α expression. Furthermore, metabolic labeling experiments with 13C-glucose showed that differential glucose routing favored alanine formation at the expense of lactate production. Additional analysis revealed increases in t...

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Research paper thumbnail of Effects of fructose on the energy metabolism and acid-base status of the perfused starved-rat liver. A 31 phosphorus nuclear magnetic resonance study

Biochemical Journal, 1980

Fructose metabolism has been studied with 31P n.m.r. in perfused livers from rats starved for 48h... more Fructose metabolism has been studied with 31P n.m.r. in perfused livers from rats starved for 48h. The time course of changes in liver ATP, Pi and sugar phosphate (fructose l-phosphate) concentrations, and intracellular pH were followed in each perfusion after infusion of fructose to give an initial concentration of either 5mM or 10mM. Rapid falls in the concentrations of ATP and Pi and intracellular pH occurred after infusion of fructose, reaching a minimum after 4-5 min, which was lower in the 10mM group than in the 5mM group. These changes were accompanied by a rapid rise in fructose 1-phosphate, reaching a plateau also after 4-5 min. At both concentrations of fructose, after the early falls, some recovery of ATP, Pi and intracellular pH occurred; this was complete for Pi and intracellular pH in the 5mM-fructose experiments (within 12-30 min). Complete restoration of ATP to the pre-fructose value was not achieved in either the 5mM of 10mM groups. Measurements of the uptake of lac...

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Research paper thumbnail of Are cancer cells acidic?

British Journal of Cancer, 1991

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Research paper thumbnail of Effect of Radiofrequency Transmit Field Correction on Quantitative Dynamic Contrast-enhanced MR Imaging of the Breast at 3.0 T

Radiology, Jan 16, 2015

Purpose To investigate the effects of radiofrequency transmit field (B1(+)) correction on (a) the... more Purpose To investigate the effects of radiofrequency transmit field (B1(+)) correction on (a) the measured T1 relaxation times of normal breast tissue and malignant lesions and (b) the pharmacokinetically derived parameters of malignant breast lesions at 3 T. Materials and Methods Ethics approval and informed consent were obtained. Between May 2013 and January 2014, 30 women (median age, 58 years; range, 32-83 years) with invasive ductal carcinoma of at least 10 mm were recruited to undergo dynamic contrast material-enhanced magnetic resonance (MR) imaging before surgery. B1(+) and T1 mapping sequences were performed to determine the effect of B1(+) correction on the native tissue relaxation time (T10) of fat, parenchyma, and malignant lesions in both breasts. Pharmacokinetic parameters were calculated before and after correction for B1(+) variations. Results were correlated with histologic grade by using the Kruskal-Wallis test. Results Measurements showed a mean 37% flip angle dif...

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Research paper thumbnail of The response to carbogen breathing in experimental tumour models monitored by gradient-recalled echo magnetic resonance imaging

British Journal of Cancer, 1997

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Research paper thumbnail of Growth studies of subcutaneous rat tumours: comparison of 31P-NMR spectroscopy, acid extracts and histology

British Journal of Cancer, 1989

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