title: Detection of tumor response to a vascular disrupting agent by hyperpolarized 13C magnetic resonance spectroscopy.
abstract: Nuclear spin hyperpolarization can dramatically increase the sensitivity of the (13)C magnetic resonance experiment, allowing dynamic measurements of the metabolism of hyperpolarized (13)C-labeled substrates in vivo. Here, we report a preclinical study of the response of lymphoma tumors to the vascular disrupting agent (VDA), combretastatin-A4-phosphate (CA4P), as detected by measuring changes in tumor metabolism of hyperpolarized [1-(13)C]pyruvate and [1,4-(13)C(2)]fumarate. These measurements were compared with dynamic contrast agent-enhanced magnetic resonance imaging (DCE-MRI) measurements of tumor vascular function and diffusion-weighted MRI (DW-MRI) measurements of the tumor cell necrosis that resulted from subsequent loss of tumor perfusion. The rate constant describing flux of hyperpolarized (13)C label between [1-(13)C]pyruvate and lactate was decreased by 34% within 6 hours of CA4P treatment and remained at this lower level at 24 hours. The rate constant describing production of labeled malate from hyperpolarized [1,4-(13)C(2)]fumarate increased 1.6-fold and 2.5-fold at 6 and 24 hours after treatment, respectively, and correlated with the degree of necrosis detected in histologic sections. Although DCE-MRI measurements showed a substantial reduction in perfusion at 6 hours after treatment, which had recovered by 24 hours, DW-MRI showed no change in the apparent diffusion coefficient of tumor water at 6 hours after treatment, although there was a 32% increase at 24 hours (P < 0.02) when regions of extensive necrosis were observed by histology. Measurements of hyperpolarized [1-(13)C]pyruvate and [1,4-(13)C(2)]fumarate metabolism may provide, therefore, a more sustained and sensitive indicator of response to a VDA than DCE-MRI or DW-MRI, respectively.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Bohndiek
authors.forename: Mikko I
authors.initials: MI
authors.lastname: Kettunen
authors.forename: De-en
authors.initials: DE
authors.lastname: Hu
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Witney
authors.forename: Brett W C
authors.initials: BW
authors.lastname: Kennedy
authors.forename: Ferdia A
authors.initials: FA
authors.lastname: Gallagher
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brindle
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D002247:Carbon Isotopes; D003287:Contrast Media; D038524:Diffusion Magnetic Resonance Imaging; D005650:Fumarates / Q000008:administration & dosage / Q000494:pharmacology; D007275:Injections, Intravenous; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D019289:Pyruvic Acid / Q000008:administration & dosage / Q000494:pharmacology; D013267:Stilbenes / Q000737:chemistry / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D020533:Angiogenesis Inhibitors; D002247:Carbon Isotopes; D003287:Contrast Media; D005650:Fumarates; D013267:Stilbenes; D019289:Pyruvic Acid; C058728:fosbretabulin