Tumor 31P NMR pH measurements in vivo: A comparison of inorganic phosphate and intracellular 2‐deoxyglucose‐6‐phosphate as pHnmr indicators in murine radiation‐induced fibrosarcoma‐1

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Abstract
Uncertainty regarding the intracellular/extracellular distribution of inorganic phosphate (Pi) in tumors has raised concerns that pH calculated from the tumor Pi chemical shift may not accurately represent the intracellular pH (pHin). This issue was addressed in subcutaneously transplanted murine radiation induced fibrosarcoma‐1 by directly comparing pH measured via Pi with pH measured via the in situ generated intracellular xenometabolite 2‐deoxyglucose‐6‐phosphate (2DG6P). In 131 comparative measurements employing eight tumor‐bearing mice under both control and hyperglycemic conditions (the latter to extend the range of tumor pH examined), the pH as derived from either 2DG6P or Pi showed only a small, but statistically significant, difference (0.07 ± 0.11 SD; P = 0.0001). Scatter in the comparative analysis over the pH range examined (ca. 5.5‐7.5) was not uniform. Above pH 6.6, 2DG6P indicated a pH lower than that of Pi by 0.088 ± 0.105 SD (n = 107, P = 0.0001); below pH 6.6, 2DG6P indicated a pH essentially identical to and not statistically different from that of Pi (mean difference 0.003 ± 0.128 SD (n = 24, P = 0.92)). Evidence is presented in support of this differential arising from a systematic measurement error due to peak overlap between 2DG6P and endogenous phosphomonoester species. These results support the use of Pi as a tumor 31P NMR pHin indicator, at least in RIF‐1 tumors under control and hyperglycemic conditions.