title: Production of hyperpolarized [1,4-13C2]malate from [1,4-13C2]fumarate is a marker of cell necrosis and treatment response in tumors.
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 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.
authors.affiliation: Cancer Research United Kingdom, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, United Kingdom.
authors.forename: Ferdia A
authors.initials: FA
authors.lastname: Gallagher
authors.forename: Mikko I
authors.initials: MI
authors.lastname: Kettunen
authors.forename: De-En
authors.initials: DE
authors.lastname: Hu
authors.forename: Pernille R
authors.initials: PR
authors.lastname: Jensen
authors.forename: René In 't
authors.initials: RI
authors.lastname: Zandt
authors.forename: Magnus
authors.initials: M
authors.lastname: Karlsson
authors.forename: Anna
authors.initials: A
authors.lastname: Gisselsson
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Nelson
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Witney
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Bohndiek
authors.forename: Georg
authors.initials: G
authors.lastname: Hansson
authors.forename: Torben
authors.initials: T
authors.lastname: Peitersen
authors.forename: Mathilde H
authors.initials: MH
authors.lastname: Lerche
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brindle
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000378:metabolism; D002247:Carbon Isotopes / Q000737:chemistry / Q000378:metabolism; D005047:Etoposide / Q000627:therapeutic use; D005260:Female; D005649:Fumarate Hydratase / Q000378:metabolism; D005650:Fumarates / Q000737:chemistry / Q000378:metabolism; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology; D008293:Malates / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000378:metabolism* / Q000473:pathology; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019906:Nuclear Magnetic Resonance, Biomolecular; D014020:Tissue Extracts / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D002247:Carbon Isotopes; D005650:Fumarates; D008293:Malates; D014020:Tissue Extracts; D005047:Etoposide; C030298:malic acid; D005649:Fumarate Hydratase