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Production of hyperpolarized [1,4-13C2]malate from [1,4-13C2]fumarate is a marker of cell necrosis and treatment response in tumors

Gallagher, Ferdia A; Kettunen, Mikko I. ; Hu, De-En; Jensen, Pernille R; Zandt, René In 't LU ; Karlsson, Magnus; Gisselsson, Anna; Nelson, Sarah K; Witney, Timothy H and Bohndiek, Sarah E, et al. (2009) In Proceedings of the National Academy of Sciences of the United States of America 106(47). p.6-19801
Abstract

Dynamic nuclear polarization of (13)C-labeled cell substrates has been shown to massively increase their sensitivity to detection in NMR experiments. The sensitivity gain is sufficiently large that if these polarized molecules are injected intravenously, their spatial distribution and subsequent conversion into other cell metabolites can be imaged. We have used this method to image the conversion of fumarate to malate in a murine lymphoma tumor in vivo after i.v. injection of hyperpolarized [1,4-(13)C(2)]fumarate. In isolated lymphoma cells, the rate of labeled malate production was unaffected by coadministration of succinate, which competes with fumarate for transport into the cell. There was, however, a correlation with the percentage... (More)

Dynamic nuclear polarization of (13)C-labeled cell substrates has been shown to massively increase their sensitivity to detection in NMR experiments. The sensitivity gain is sufficiently large that if these polarized molecules are injected intravenously, their spatial distribution and subsequent conversion into other cell metabolites can be imaged. We have used this method to image the conversion of fumarate to malate in a murine lymphoma tumor in vivo after i.v. injection of hyperpolarized [1,4-(13)C(2)]fumarate. In isolated lymphoma cells, the rate of labeled malate production was unaffected by coadministration of succinate, which competes with fumarate for transport into the cell. There was, however, a correlation with the percentage of cells that had lost plasma membrane integrity, suggesting that the production of labeled malate from fumarate is a sensitive marker of cellular necrosis. Twenty-four hours after treating implanted lymphoma tumors with etoposide, at which point there were significant levels of tumor cell necrosis, there was a 2.4-fold increase in hyperpolarized [1,4-(13)C(2)]malate production compared with the untreated tumors. Therefore, the formation of hyperpolarized (13)C-labeled malate from [1,4-(13)C(2)]fumarate appears to be a sensitive marker of tumor cell death in vivo and could be used to detect the early response of tumors to treatment. Given that fumarate is an endogenous molecule, this technique has the potential to be used clinically.

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keywords
Animals, Antineoplastic Agents, Phytogenic, Biomarkers, Tumor, Carbon Isotopes, Etoposide, Female, Fumarate Hydratase, Fumarates, Lymphoma, Malates, Mice, Mice, Inbred C57BL, Necrosis, Neoplasm Transplantation, Neoplasms, Nuclear Magnetic Resonance, Biomolecular, Tissue Extracts, Treatment Outcome, Journal Article, Research Support, Non-U.S. Gov't
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Proceedings of the National Academy of Sciences of the United States of America
volume
106
issue
47
pages
6 pages
publisher
National Acad Sciences
external identifiers
  • scopus:73949133557
ISSN
1091-6490
DOI
10.1073/pnas.0911447106
language
English
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no
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5154ccea-b0e5-4bea-b6e6-e2a72d75fba7
date added to LUP
2017-03-16 11:26:20
date last changed
2017-12-10 05:06:47
@article{5154ccea-b0e5-4bea-b6e6-e2a72d75fba7,
  abstract     = {<p>Dynamic nuclear polarization of (13)C-labeled cell substrates has been shown to massively increase their sensitivity to detection in NMR experiments. The sensitivity gain is sufficiently large that if these polarized molecules are injected intravenously, their spatial distribution and subsequent conversion into other cell metabolites can be imaged. We have used this method to image the conversion of fumarate to malate in a murine lymphoma tumor in vivo after i.v. injection of hyperpolarized [1,4-(13)C(2)]fumarate. In isolated lymphoma cells, the rate of labeled malate production was unaffected by coadministration of succinate, which competes with fumarate for transport into the cell. There was, however, a correlation with the percentage of cells that had lost plasma membrane integrity, suggesting that the production of labeled malate from fumarate is a sensitive marker of cellular necrosis. Twenty-four hours after treating implanted lymphoma tumors with etoposide, at which point there were significant levels of tumor cell necrosis, there was a 2.4-fold increase in hyperpolarized [1,4-(13)C(2)]malate production compared with the untreated tumors. Therefore, the formation of hyperpolarized (13)C-labeled malate from [1,4-(13)C(2)]fumarate appears to be a sensitive marker of tumor cell death in vivo and could be used to detect the early response of tumors to treatment. Given that fumarate is an endogenous molecule, this technique has the potential to be used clinically.</p>},
  author       = {Gallagher, Ferdia A and Kettunen, Mikko I.  and Hu, De-En and Jensen, Pernille R and Zandt, René In 't and Karlsson, Magnus and Gisselsson, Anna and Nelson, Sarah K and Witney, Timothy H and Bohndiek, Sarah E and Hansson, Georg and Peitersen, Torben and Lerche, Mathilde H and Brindle, Kevin M},
  issn         = {1091-6490},
  keyword      = {Animals,Antineoplastic Agents, Phytogenic,Biomarkers, Tumor,Carbon Isotopes,Etoposide,Female,Fumarate Hydratase,Fumarates,Lymphoma,Malates,Mice,Mice, Inbred C57BL,Necrosis,Neoplasm Transplantation,Neoplasms,Nuclear Magnetic Resonance, Biomolecular,Tissue Extracts,Treatment Outcome,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {11},
  number       = {47},
  pages        = {6--19801},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {Production of hyperpolarized [1,4-13C2]malate from [1,4-13C2]fumarate is a marker of cell necrosis and treatment response in tumors},
  url          = {http://dx.doi.org/10.1073/pnas.0911447106},
  volume       = {106},
  year         = {2009},
}