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

(2)H magnetic resonance spectroscopic imaging has been shown recently to be a viable technique for metabolic imaging in the clinic. We show here that (2)H MR spectroscopy and spectroscopic imaging measurements of [2,3-(2)H(2)]malate production from [2,3-(2)H(2)]fumarate can be used to detect tumor cell death in vivo via the production of labeled malate. Production of [2,3-(2)H(2)]malate, following injection of [2,3-(2)H(2)]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 (2)H MR spectroscopy at 7 T. Malate production was also imaged in EL4 tumors using a fast (2)H 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 (P = 0.0024, n = 3), and from 0.019 ± 0.03 to 0.25 ± 0.23 in MDA-MB-231 tumors (P = 0.0001, n = 5) and from 0.016 ± 0.04 to 0.28 ± 0.26 in Colo205 tumors (P = 0.0002, n = 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. (2)H MR measurements of [2,3-(2)H(2)]malate production from [2,3-(2)H(2)]fumarate provide a potentially less expensive and more sensitive method for detecting cell death in vivo than (13)C MR measurements of hyperpolarized [1,4-(13)C(2)]fumarate metabolism, which have been used previously for this purpose.