Preclinical Development Detection of Tumor Response to a Vascular Disrupting Agent by Hyperpolarized C Magnetic Resonance Spectroscopy

Nuclear spin hyperpolarization can dramatically increase the sensitivity of the C magnetic resonance experiment, allowing dynamic measurements of the metabolism of hyperpolarized 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-C]pyruvate and [1,4-C2]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 C label between [1-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-C2]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, DWMRI 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-C]pyruvate and [1,4-C2]fumaratemetabolismmay provide, therefore, a more sustained and sensitive indicator of response to a VDA than DCE-MRI or DW-MRI, respectively. Mol Cancer Ther; 9(12); 3278–88. 2010 AACR.