Abstract
PurposeTo estimate the rate constant for pyruvate to lactate conversion in tumours in response to a hypoxic challenge, using hyperpolarised 13C1-pyruvate and magnetic resonance spectroscopy. Methods and materialsHypoxic inspired gas was used to manipulate rat P22 fibrosarcoma oxygen tension (pO2), confirmed by luminescence decay of oxygen-sensitive probes. Hyperpolarised 13C1-pyruvate was injected into the femoral vein of anaesthetised rats and slice-localised 13C 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. ResultsMABP, 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. ConclusionThe rate constant for pyruvate to lactate conversion, kpl, responds significantly to a rapid reduction in tumour oxygenation.
Highlights
To estimate the rate constant for pyruvate to lactate conversion in tumours in response to a hypoxic challenge, using hyperpolarised 13C1-pyruvate and magnetic resonance spectroscopy
Mean arterial blood pressure (MABP), ArtpO2 and tumour pO2 decreased significantly during hypoxia. kpl increased significantly (p < 0.01) from 0.029 ± 0.002 sÀ1 to 0.049 ± 0.006 sÀ1 when animals breathing air were switched to hypoxic conditions, whereas pyruvate and lactate concentrations were minimally affected by hypoxia
Available data suggest that the majority of tumour energy (ATP) production is via oxidative phosphorylation (OXPHOS) [12] and that there is a switch away from OXPHOS towards increased glucose consumption and lactate production under acute hypoxic conditions [13,14]
Summary
To estimate the rate constant for pyruvate to lactate conversion in tumours in response to a hypoxic challenge, using hyperpolarised 13C1-pyruvate and magnetic resonance spectroscopy. Kpl increased significantly (p < 0.01) from 0.029 ± 0.002 sÀ1 to 0.049 ± 0.006 sÀ1 (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. Dissolution dynamic nuclear polarisation (dDNP) of metabolic substrates combined with MRS/MRSI is established pre-clinically for monitoring in vivo metabolism [7] and its first clinical use has been published [8] This technique potentially provides a complementary MRS/MRSI-based method for monitoring induced changes in tumour metabolism that are influenced by oxygenation status. The aim of the current study was to establish how the rate constant for tumour conversion of pyruvate to lactate responds to an acute hypoxic challenge in a rat tumour model
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