Metabolic response of glioma to dichloroacetate measured in vivo by hyperpolarized 13C magnetic resonance spectroscopic imaging

Park, Jae Mo; Recht, Lawrence D.; Josan, Sonal; Merchant, Milton; Jang, Taichang; Yen, Yi Fen; Hurd, Ralph E.; Spielman, Daniel M.; Mayer, Dirk

doi:10.1093/neuonc/nos319

Cited by 60 publications

(125 citation statements)

References 62 publications

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“…For the measurements of metabolic kinetics using the dynamic free induction decay (FID), the NMR signal acquisition used the following parameters: 10 deg radiofrequency (RF) hard pulse, temporal resolution=3 s, spectral width/points=10 kHz/4096, acquisition time=4 min. A volumetric single time-point spiral CSI sequence (field of view=80×80×60 mm 3 , matrix size=16×16×12, spectral bandwidth/points=972.7 Hz/96, acquisition time=4 s, 20 deg hard pulse) with a circularly reduced k-space sampling scheme for the shortened scan time was used to acquire the CSI (Park et al, 2013b). To obtain the maximum signal of 13 C-labeled metabolic products, the CSI scan was started 25 s after the start of the injection.…”

Section: Nmr Protocolsmentioning

confidence: 99%

Hyperpolarized 13C NMR observation of lactate kinetics in skeletal muscle

Park

Josan

Mayer

et al. 2015

Journal of Experimental Biology

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The production of glycolytic end products, such as lactate, usually evokes a cellular shift from aerobic to anaerobic ATP generation and O 2 insufficiency. In the classical view, muscle lactate must be exported to the liver for clearance. However, lactate also forms under well-oxygenated conditions, and this has led investigators to postulate lactate shuttling from non-oxidative to oxidative muscle fiber, where it can serve as a precursor. Indeed, the intracellular lactate shuttle and the glycogen shunt hypotheses expand the vision to include a dynamic mobilization and utilization of lactate during a muscle contraction cycle. Testing the tenability of these provocative ideas during a rapid contraction cycle has posed a technical challenge. The present study reports the use of hyperpolarized [1- 13 C]lactate increases sharply and acetyl-L-carnitine, acetoacetate and glutamate levels also rise. Such a quick mobilization of pyruvate and lactate toward oxidative metabolism supports the postulated role of lactate in the glycogen shunt and the intracellular lactate shuttle models. The study thus introduces an innovative DNP approach to measure metabolite transients, which will help delineate the cellular and physiological role of lactate and glycolytic end products.

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Section: Nmr Protocolsmentioning

confidence: 99%

Hyperpolarized 13C NMR observation of lactate kinetics in skeletal muscle

Park

Josan

Mayer

et al. 2015

Journal of Experimental Biology

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“…By inhibiting PDK, the drug maintains PDC in its active form and facilitates mitochondrial oxidation of glucose-derived pyruvate and lactate via the tricarboxylic acid (TCA) cycle [reviewed in 9]. DCA readily crosses the blood–brain barrier, can be measured in cerebrospinal fluid and activates PDC in brain [9, 10]. DCA has a plasma half-life of ~1 h in drug-naïve individuals, but may increase several-fold with chronic administration [11, 12].…”

Section: Introductionmentioning

confidence: 99%

Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors

et al. 2013

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Summary Background Recurrent malignant brain tumors (RMBTs) carry a poor prognosis. Dichloroacetate (DCA) activates mitochondrial oxidative metabolism and has shown activity against several human cancers. Design We conducted an open-label study of oral DCA in 15 adults with recurrent WHO grade III – IV gliomas or metastases from a primary cancer outside the central nervous system. The primary objective was detection of a dose limiting toxicity for RMBTs at 4 weeks of treatment, defined as any grade 4 or 5 toxicity, or grade 3 toxicity directly attributable to DCA, based on the National Cancer Institute’s Common Toxicity Criteria for Adverse Events, version 4.0. Secondary objectives involved safety, tolerability and hypothesis-generating data on disease status. Dosing was based on haplotype variation in glutathione transferase zeta 1/maleylacetoacetate isomerase (GSTZ1/MAAI), which participates in DCA and tyrosine catabolism. Results Eight patients completed at least 1 four week cycle. During this time, no dose-limiting toxicities occurred. No patient withdrew because of lack of tolerance to DCA, although 2 subjects experienced grade 0–1 distal parasthesias that led to elective withdrawal and/or dose-adjustment. All subjects completing at least 1 four week cycle remained clinically stable during this time and remained on DCA for an average of 75.5 days (range 26–312). Conclusions Chronic, oral DCA is feasible and well-tolerated in patients with recurrent malignant gliomas and other tumors metastatic to the brain using the dose range established for metabolic diseases. The importance of genetic-based dosing is confirmed and should be incorporated into future trials of chronic DCA administration.

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“…To date, most preclinical developments have focused on samples of neat pyruvic acid (PA) to which suitable persistent radicals are added (6,(9)(10)(11)(12)(13)(14)(15)(16). In the dissolution step of the dissolution DNP method, the acid is transformed into its salt in physiological buffer.…”

mentioning

confidence: 99%

Hyperpolarization without persistent radicals for in vivo real-time metabolic imaging

Eichhorn

Takado

Salameh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

105

171

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Hyperpolarized substrates prepared via dissolution dynamic nuclear polarization have been proposed as magnetic resonance imaging (MRI) agents for cancer or cardiac failure diagnosis and therapy monitoring through the detection of metabolic impairments in vivo. The use of potentially toxic persistent radicals to hyperpolarize substrates was hitherto required. We demonstrate that by shining UV light for an hour on a frozen pure endogenous substance, namely the glucose metabolic product pyruvic acid, it is possible to generate a concentration of photo-induced radicals that is large enough to highly enhance the 13 C polarization of the substance via dynamic nuclear polarization. These radicals recombine upon dissolution and a solution composed of purely endogenous products is obtained for performing in vivo metabolic hyperpolarized 13 C MRI with high spatial resolution. Our method opens the way to safe and straightforward preclinical and clinical applications of hyperpolarized MRI because the filtering procedure mandatory for clinical applications and the associated pharmacological tests necessary to prevent contamination are eliminated, concurrently allowing a decrease in the delay between preparation and injection of the imaging agents for improved in vivo sensitivity.is a very powerful imaging modality in terms of temporal and spatial resolution of anatomical structures. The modality is widespread, well established in clinical environments, and paramagnetic agents are used extensively for enhanced contrast or perfusion examination. MR is also a unique technique to obtain in vivo metabolic maps using the spectroscopic information that can be extracted from the time-domain acquisitions. In particular, it is possible to monitor the biochemical transformations of specific substrates that are delivered to subjects. Because it gives access to the kinetics of the conversion of substrates into metabolites, MR spectroscopy (MRS) of the carbon nuclei ( 13 C) is one of the most powerful techniques to investigate intermediary metabolism (1).The well-known weakness of MR as a spectroscopic technique is its relatively low sensitivity. It can be offset by so-called hyperpolarization methods, in particular the one based on dynamic nuclear polarization (DNP) (2), which is now commonly referred to as dissolution DNP and was first proposed about a decade ago (3). The hyperpolarized substrates obtained following dissolution DNP are biomolecules in aqueous solution with a largely out-ofequilibrium nuclear spin polarization corresponding to an enhancement of several orders of magnitude compared with the thermal equilibrium polarization attainable in MRI scanners. A basic requirement for DNP is the presence of unpaired electron spins in the sample to be hyperpolarized. These polarizing agents are usually incorporated in the form of persistent radicals. An inherent limit of any hyperpolarization method is that the intrinsic longitudinal nuclear spin relaxation will annihilate the polarization enhancement in the course of time to reach t...

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Metabolic response of glioma to dichloroacetate measured in vivo by hyperpolarized 13C magnetic resonance spectroscopic imaging

Cited by 60 publications

References 62 publications

Hyperpolarized 13C NMR observation of lactate kinetics in skeletal muscle

Hyperpolarized 13C NMR observation of lactate kinetics in skeletal muscle

Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors

Hyperpolarization without persistent radicals for in vivo real-time metabolic imaging

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