Detecting treatment response in a model of human breast adenocarcinoma using hyperpolarised [1-13C]pyruvate and [1,4-13C2]fumarate

Abstract

Background:The recent introduction of a dynamic nuclear polarisation technique has permitted noninvasive imaging of tumour cell metabolism in vivo following intravenous administration of 13C-labelled cell substrates.Methods:Changes in hyperpolarised [1-13C]pyruvate and [1,4-13C2]fumarate metabolism were evaluated in both MDA-MB-231 cells and in implanted MDA-MB-231 tumours following doxorubicin treatment.Results:Treatment of MDA-MB-231 cells resulted in the induction of apoptosis, which was accompanied by a decrease in hyperpolarised 13C label flux between [1-13C]pyruvate and lactate, which was correlated with a decrease in the cellular NAD(H) coenzyme pool. There was also an increase in the rate of fumarate conversion to malate, which accompanied the onset of cellular necrosis. In vivo, the decrease in 13C label exchange between pyruvate and lactate and the increased flux between fumarate and malate, following drug treatment, were shown to occur in the absence of any detectable change in tumour size.Conclusion:We show here that the early responses of a human breast adenocarcinoma tumour model to drug treatment can be followed by administration of both hyperpolarised [1-13C]pyruvate and [1,4-13C2]fumarate. These techniques could be used, therefore, in the clinic to detect the early responses of breast tumours to treatment.

Magnetic resonance imaging with hyperpolarized [1,4- 13 C 2 ]fumarate allows detection of early renal acute tubular necrosis

“…Magnetic resonance spectroscopy (MRS) has been used to detect biochemical changes associated with disease in a variety of organs, including the kidneys (17), but it is limited by its low sensitivity (18). Hyperpolarization of 13 C-labeled molecules radically enhances their detection by 13 C-MRS (19) and has allowed metabolic imaging of several substrates in vivo (20), including fumarate and pyruvate (21)(22)(23) (22). This has been demonstrated following chemotherapy-induced necrosis in tumor cells in vitro and in implanted tumors in vivo (22,23).…”

“…Hyperpolarization of 13 C-labeled molecules radically enhances their detection by 13 C-MRS (19) and has allowed metabolic imaging of several substrates in vivo (20), including fumarate and pyruvate (21)(22)(23) (22). This has been demonstrated following chemotherapy-induced necrosis in tumor cells in vitro and in implanted tumors in vivo (22,23). Pyruvate, a product of glycolysis, is reduced to lactate by NADH in the reaction catalyzed by lactate dehydrogenase (LDH).…”

In vivo single-shot 13C spectroscopic imaging of hyperpolarized metabolites by spatiotemporal encoding

“…Further developments are in progress to exploit additional benefits of spatiotemporal encoding, such as a built-in restricted FOV capability [24,26], multi-echo experiments and parallel imaging acquisition [34]. Representative metabolic images from a rat following injection of hyperpolarized [1][2][3][4][5][6][7][8][9][10][11][12][13] …”

“…Dissolution DNP has opened new horizons in dynamic metabolic imaging through 13 C spectral observations of hyperpolarized compounds in vivo [1][2]. DNP can result in signal enhancements >10,000 for 13 C; an unprecedented increase that is leading to new opportunities for imaging pathology and monitoring treatment [3][4][5][6][7]. Pyruvic acid has emerged as the principal 13 C-labeled agent in d-DNP, but there is significant on-going research to develop other compounds for dynamic imaging of metabolism [8][9][10].…”

Using magnetic resonance imaging and spectroscopy in cancer diagnostics and monitoring

“…Animal models have also been studied by 13 C labeled fumarate which gives specific information on necrosis 130 and 13 C labeled bicarbonate which gives information on pH. 131 These techniques have high potential and clinical studies are already underway using 13 C labeled pyruvate to investigate prostate cancer.…”