Open AccessMonitoring tumor cell death in murine tumor models using deuterium magnetic resonance spectroscopy and spectroscopic imaging
Author(s) -
Friederike Hesse,
Vencel Somai,
Felix Kreis,
Flaviu Bulat,
Alan J. Wright,
Kevin M. Brindle
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2014631118
Subject(s) - in vivo , programmed cell death , nuclear magnetic resonance , nuclear magnetic resonance spectroscopy , magnetic resonance imaging , cell , chemistry , tumor cells , cancer research , pathology , biology , medicine , apoptosis , biochemistry , radiology , physics , microbiology and biotechnology
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.