title: Measurement of the acute metabolic response to hypoxia in rat tumours in vivo using magnetic resonance spectroscopy and hyperpolarised pyruvate.
abstract: OBJECTIVE
  To estimate the rate constant for pyruvate to lactate conversion in tumours in response to a hypoxic challenge, using hyperpolarised (13)C1-pyruvate and magnetic resonance spectroscopy.
  
  
  METHODS
  Hypoxic inspired gas was used to manipulate rat P22 fibrosarcoma oxygen tension (pO2), confirmed by luminescence decay of oxygen-sensitive probes. Hyperpolarised (13)C1-pyruvate was injected into the femoral vein of anaesthetised rats and slice-localised (13)C magnetic resonance (MR) spectra acquired. Spectral integral versus time curves for pyruvate and lactate were fitted to a precursor-product model to estimate the rate constant for tumour conversion of pyruvate to lactate (kpl). Mean arterial blood pressure (MABP) and oxygen tension (ArtpO2) were monitored. Pyruvate and lactate concentrations were measured in freeze-clamped tumours.
  
  
  RESULTS
  MABP, ArtpO2 and tumour pO2 decreased significantly during hypoxia. kpl increased significantly (p<0.01) from 0.029±0.002s(-1) to 0.049±0.006s(-1) (mean±SEM) when animals breathing air were switched to hypoxic conditions, whereas pyruvate and lactate concentrations were minimally affected by hypoxia. Both ArtpO2 and MABP influenced the estimate of kpl, with a strong negative correlation between kpl and the product of ArtpO2 and MABP under hypoxia.
  
  
  CONCLUSIONS
  The rate constant for pyruvate to lactate conversion, kpl, responds significantly to a rapid reduction in tumour oxygenation.
authors.affiliation: Tumour Microcirculation Group, Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, UK.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Bluff
authors.affiliation: Academic Unit of Radiology, Department of Cardiovascular Science, University of Sheffield, UK. Electronic address: steven.reynolds@sheffield.ac.uk.
authors.forename: Steven
authors.initials: S
authors.lastname: Reynolds
authors.affiliation: Tumour Microcirculation Group, Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Metcalf
authors.affiliation: Tumour Microcirculation Group, Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, UK.
authors.forename: Tooba
authors.initials: T
authors.lastname: Alizadeh
authors.affiliation: Tumour Microcirculation Group, Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, UK.
authors.forename: Samira M
authors.initials: SM
authors.lastname: Kazan
authors.affiliation: Academic Unit of Radiology, Department of Cardiovascular Science, University of Sheffield, UK.
authors.forename: Adriana
authors.initials: A
authors.lastname: Bucur
authors.affiliation: Tumour Microcirculation Group, Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, UK.
authors.forename: Emily G
authors.initials: EG
authors.lastname: Wholey
authors.affiliation: Tumour Microcirculation Group, Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, UK.
authors.forename: Becky A S
authors.initials: BA
authors.lastname: Bibby
authors.affiliation: Tumour Microcirculation Group, Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, UK.
authors.forename: Leigh
authors.initials: L
authors.lastname: Williams
authors.affiliation: Academic Unit of Radiology, Department of Cardiovascular Science, University of Sheffield, UK.
authors.forename: Martyn N
authors.initials: MN
authors.lastname: Paley
authors.affiliation: Tumour Microcirculation Group, Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, UK.
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Tozer
mesh_terms: D000818:Animals; D002247:Carbon Isotopes; D004195:Disease Models, Animal; D005354:Fibrosarcoma / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D019289:Pyruvic Acid / Q000378:metabolism*; D051381:Rats
chemical_list: D002247:Carbon Isotopes; D019344:Lactic Acid; D019289:Pyruvic Acid
keywords: Dynamic nuclear polarisation; Magnetic resonance spectroscopy; Pyruvate metabolism; Tumour oxygenation
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