Measurement of the acute metabolic response to hypoxia in rat tumours in vivo using magnetic resonance spectroscopy and hyperpolarised pyruvate

PURPOSE: To estimate the rate constant for pyruvate to lactate conversion in tumours in response to a hypoxic challenge, using hyperpolarised (13)C(1)-pyruvate and magnetic resonance spectroscopy. METHODS AND MATERIALS: Hypoxic inspired gas was used to manipulate rat P22 fibrosarcoma oxygen tension (pO(2)), confirmed by luminescence decay of oxygen-sensitive probes. Hyperpolarised (13)C(1)-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 (k(pl)). Mean arterial blood pressure (MABP) and oxygen tension (ArtpO(2)) were monitored. Pyruvate and lactate concentrations were measured in freeze-clamped tumours. RESULTS: MABP, ArtpO(2) and tumour pO(2) decreased significantly during hypoxia. k(pl) increased significantly (p < 0.01) from 0.029 ± 0.002 s(−1) to 0.049 ± 0.006 s(−1) (mean ± SEM) when animals breathing air were switched to hypoxic conditions, whereas pyruvate and lactate concentrations were minimally affected by hypoxia. Both ArtpO(2) and MABP influenced the estimate of k(pl), with a strong negative correlation between k(pl) and the product of ArtpO(2) and MABP under hypoxia. CONCLUSION: The rate constant for pyruvate to lactate conversion, k(pl), responds significantly to a rapid reduction in tumour oxygenation.