31P magnetic resonance spectroscopy is sensitive to tumor hypoxia: Perfusion and oxygenation of rat 9L gliosarcoma after treatment with BCNU

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Abstract
The mechanism behind the relative increase in high‐energy phosphates observed by MRS in many tumors following chemotherapy is poorly understood. To test the hypothesis that this metabolic activation is associated with a decrease in tumor hypoxia, tumor blood flow and oxygenation were measured in tumors that were also analyzed by MRS. 31P MR spectra were acquired with a GE 2T CSI spectrometer from subcutaneous 9L tumors in rats 4 days following treatment with BCNU (10 mg/kg) and from age‐matched sham‐treated control tumors. BCNU‐treated tumors (n = 13) underwent a significant improvement in bioenergetic state compared to control tumors (n = 14), showing a relative increase in high‐energy phosphate (Pi/phosphocreatine) (pi (Pi/a nucleoside biphosphate) (p133Xe washout, following injection of 133Xe in saline into control and treated 9L tumors 4 days after treatment, was used to measure tumor perfusion. Sham‐treated control tumors (n = 21) were perfused at a rate of 35.4 (±6.4 SE) mL/100g/min, while BCNU‐treated tumors (n = 20) were perfused at a rate of 55.1 (±7.5 SE) mL/100g/min (T = 1.96; p pO2), measured with a polarographic electrode was found to be significantly higher in treated 9L than in sham‐treated controls. Mean tumor pO2 of sham‐treated tumors was 18.1 (±1.7 SE) mmHg (n = 00 measurements in six tumors) while mean pO2 of treated tumors was 45.1 (±2.1 SE) mmHg (n = 500 in five tumors) (T = 10.12; p<0.001). If the range 0‐5 mmHg is taken to approximate the hypoxic fraction, then control tumors are ±23% hypoxic, while treated tumors are only 2% hypoxic. These data suggest that metabolic activation of tumors following therapy may be associated with decreased tumor metabolic hypoxia.