Production of hyperpolarized [1,4-C-13(2)]malate from [1,4-C-13(2)]fumarate is a marker of cell necrosis and treatment response in tumors

Ferdia A. Gallagher, Mikko I. Kettunen, De-En Hu, Pernille Rose Jensen, Rene in't Zandt, Magnus Karlsson, Anna Gisselsson, Sarah K. Nelson, Timothy H. Witney, Sarah E. Bohndiek, Georg Hansson, Torben Peitersen, Mathilde Hauge Lerche, Kevin M. Brindle

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Dynamic nuclear polarization of C-13-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-C-13(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-C-13(2)] malate production compared with the untreated tumors. Therefore, the formation of hyperpolarized C-13-labeled malate from [1,4-C-13(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.
Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number47
Pages (from-to)19801-19806
ISSN0027-8424
DOIs
Publication statusPublished - 2009
Externally publishedYes

Keywords

  • MULTIDISCIPLINARY
  • RENAL BRUSH-BORDER
  • IN-VIVO
  • MEMBRANE-VESICLES
  • BREAST CARCINOMAS
  • TRANSPORT
  • SPECTROSCOPY
  • APOPTOSIS
  • FUMARASE
  • DEATH
  • ACID
  • magnetic resonance imaging
  • spectroscopy
  • metabolism
  • cell death
  • lymphoma
  • cell necrosis
  • dynamic nuclear polarization
  • plasma membrane integrity loss
  • treatment response
  • lymphoma tumor neoplastic disease, immune system disease, blood and lymphatic disease therapy
  • Rodentia Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Mammals, Nonhuman Vertebrates, Nonhuman Mammals, Rodents, Vertebrates) - Muridae [86375] EL-4 cell line cell_line murine lymphoma cells
  • [1,4-13-carbon] fumarate
  • [1,4-13-carbon] malate
  • cell metabolite
  • 02506, Cytology - Animal
  • 10060, Biochemistry studies - General
  • 12512, Pathology - Therapy
  • 15002, Blood - Blood and lymph studies
  • 15004, Blood - Blood cell studies
  • 15006, Blood - Blood, lymphatic and reticuloendothelial pathologies
  • 24004, Neoplasms - Pathology, clinical aspects and systemic effects
  • 24008, Neoplasms - Therapeutic agents and therapy
  • 24010, Neoplasms - Blood and reticuloendothelial neoplasms
  • 34502, Immunology - General and methods
  • 34508, Immunology - Immunopathology, tissue immunology
  • Chemical Coordination and Homeostasis
  • Transport and Circulation
  • imaging laboratory techniques, imaging and microscopy techniques
  • NMR laboratory techniques, spectrum analysis techniques
  • Biochemistry and Molecular Biophysics
  • Blood and Lymphatics
  • Immune System
  • Tumor Biology

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