Detection of tumor response to a vascular disrupting agent by hyperpolarized 13C magnetic resonance spectroscopy

Sarah E Bohndiek, Mikko I Kettunen, De-en Hu, Timothy H Witney, Brett W C Kennedy, Ferdia A Gallagher, Kevin M Brindle

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65 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)3278-3288
Number of pages11
JournalMolecular Cancer Therapeutics
Issue number12
Publication statusPublished - Dec 2010

Bibliographical note

©2010 AACR.


  • angiogenesis inhibitors
  • animals
  • carbon isotopes
  • contrast media
  • diffusion magnetic resonance imaging
  • fumarates
  • injections, intravenous
  • magnetic resonance spectroscopy
  • mice
  • neoplasms
  • neovascularization, pathologic
  • pyruvic acid
  • stilbenes
  • time factors


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