Monitoring tumor cell death in murine tumor models using deuterium magnetic resonance spectroscopy and spectroscopic imaging

Abstract

²H magnetic resonance spectroscopic imaging has been shown recently to be a viable technique for metabolic imaging in the clinic. We show here that ²H MR spectroscopy and spectroscopic imaging measurements of [2,3-²H₂]malate production from [2,3-²H₂]fumarate can be used to detect tumor cell death in vivo via the production of labeled malate. Production of [2,3-²H₂]malate, following injection of [2,3-²H₂]fumarate (1 g/kg) into tumor-bearing mice, was measured in a murine lymphoma (EL4) treated with etoposide, and in human breast (MDA-MB-231) and colorectal (Colo205) xenografts treated with a TRAILR2 agonist, using surface-coil localized ²H MR spectroscopy at 7 T. Malate production was also imaged in EL4 tumors using a fast ²H chemical shift imaging sequence. The malate/fumarate ratio increased from 0.016 ± 0.02 to 0.16 ± 0.14 in EL4 tumors 48 h after drug treatment (<i>P</i> = 0.0024, <i>n</i> = 3), and from 0.019 ± 0.03 to 0.25 ± 0.23 in MDA-MB-231 tumors (<i>P</i> = 0.0001, <i>n</i> = 5) and from 0.016 ± 0.04 to 0.28 ± 0.26 in Colo205 tumors (<i>P</i> = 0.0002, <i>n</i> = 5) 24 h after drug treatment. These increases were correlated with increased levels of cell death measured in excised tumor sections obtained immediately after imaging. ²H MR measurements of [2,3-²H₂]malate production from [2,3-²H₂]fumarate provide a potentially less expensive and more sensitive method for detecting cell death in vivo than ¹³C MR measurements of hyperpolarized [1,4-¹³C₂]fumarate metabolism, which have been used previously for this purpose.