Bluff Joanne E, Reynolds Steven, Metcalf Stephen, Alizadeh Tooba, Kazan Samira M, Bucur Adriana, Wholey Emily G, Bibby Becky A S, Williams Leigh, Paley Martyn N, Tozer Gillian M
Tumour Microcirculation Group, Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, UK.
Academic Unit of Radiology, Department of Cardiovascular Science, University of Sheffield, UK.
Radiother Oncol. 2015 Sep;116(3):392-9. doi: 10.1016/j.radonc.2015.03.011. Epub 2015 Mar 27.
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.
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.
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.
The rate constant for pyruvate to lactate conversion, kpl, responds significantly to a rapid reduction in tumour oxygenation.
使用超极化（13）C1 - 丙酮酸和磁共振波谱法，评估肿瘤中丙酮酸向乳酸转化的速率常数，以应对缺氧挑战。
使用低氧吸入气体来控制大鼠P22纤维肉瘤的氧张力（pO2），通过氧敏感探针的发光衰减来确认。将超极化（13）C1 - 丙酮酸注入麻醉大鼠的股静脉，并采集切片定位的（13）C磁共振（MR）波谱。丙酮酸和乳酸的光谱积分与时间曲线拟合到前体 - 产物模型，以估计肿瘤中丙酮酸向乳酸转化的速率常数（kpl）。监测平均动脉血压（MABP）和氧张力（ArtpO2）。在冷冻钳夹的肿瘤中测量丙酮酸和乳酸浓度。
缺氧期间，MABP、ArtpO2和肿瘤pO2显著降低。当呼吸空气的动物切换到低氧条件时，kpl从0.029±0.002s（-1）显著增加（p<0.01）至0.049±0.006s（-1）（平均值±标准误），而丙酮酸和乳酸浓度受缺氧影响最小。ArtpO2和MABP均影响kpl的估计，在缺氧条件下，kpl与ArtpO2和MABP的乘积之间存在强烈的负相关。
丙酮酸向乳酸转化的速率常数kpl对肿瘤氧合的快速降低有显著反应。
