Monitoring tumor cell death in murine tumor models using deuterium magnetic resonance spectroscopy and spectroscopic imaging
Menée à l'aide d'un modèle murin de lymphome et de xénogreffes de cancer colorectal ou de cancer du sein d'origine humaine, cette étude met en évidence l'intérêt de l'imagerie spectroscopique et de l'imagerie par résonance magnétique du deutérium pour suivre après traitement l'évolution du rapport malate[2,3-2H2]/fumarate[2,3-2H2] et en déduire la mort des cellules cancéreuses
There is an unmet clinical need for sensitive methods for detecting cell death in vivo, for example, in disease and following tumor treatment. We show here that deuterium magnetic resonance measurements at 7 T of labeled malate production from injected 2H-labeled fumarate provide a sensitive method for detecting tumor cell death in vivo following treatment. Malate production was relatively slow in viable cells but was markedly increased in necrotic tissue.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 (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. 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.All study data are included in the article and/or SI Appendix.
Proceedings of the National Academy of Sciences , résumé, 2020