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

Research output: Contribution to journalArticle

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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.
Original languageEnglish
Pages (from-to)3278-3288
Number of pages11
JournalMolecular Cancer Therapeutics
Volume9
Issue number12
DOIs
Publication statusPublished - Dec 2010

Fingerprint

Blood Vessels
Magnetic Resonance Spectroscopy
Fumarates
Diffusion Magnetic Resonance Imaging
Pyruvic Acid
Contrast Media
Neoplasms
Necrosis
Magnetic Resonance Imaging
Perfusion
Therapeutics
Lactic Acid
Lymphoma
Histology
Water
fosbretabulin

Keywords

  • 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

Cite this

Bohndiek, S. E., Kettunen, M. I., Hu, D., Witney, T. H., Kennedy, B. W. C., Gallagher, F. A., & Brindle, K. M. (2010). Detection of tumor response to a vascular disrupting agent by hyperpolarized 13C magnetic resonance spectroscopy. Molecular Cancer Therapeutics, 9(12), 3278-3288. https://doi.org/10.1158/1535-7163.MCT-10-0706

Detection of tumor response to a vascular disrupting agent by hyperpolarized 13C magnetic resonance spectroscopy. / Bohndiek, Sarah E; Kettunen, Mikko I; Hu, De-en; Witney, Timothy H; Kennedy, Brett W C; Gallagher, Ferdia A; Brindle, Kevin M.

In: Molecular Cancer Therapeutics, Vol. 9, No. 12, 12.2010, p. 3278-3288.

Research output: Contribution to journalArticle

Bohndiek, SE, Kettunen, MI, Hu, D, Witney, TH, Kennedy, BWC, Gallagher, FA & Brindle, KM 2010, 'Detection of tumor response to a vascular disrupting agent by hyperpolarized 13C magnetic resonance spectroscopy', Molecular Cancer Therapeutics, vol. 9, no. 12, pp. 3278-3288. https://doi.org/10.1158/1535-7163.MCT-10-0706
Bohndiek, Sarah E ; Kettunen, Mikko I ; Hu, De-en ; Witney, Timothy H ; Kennedy, Brett W C ; Gallagher, Ferdia A ; Brindle, Kevin M. / Detection of tumor response to a vascular disrupting agent by hyperpolarized 13C magnetic resonance spectroscopy. In: Molecular Cancer Therapeutics. 2010 ; Vol. 9, No. 12. pp. 3278-3288.
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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.",
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