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 (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.

• Authors: Friederike Hesse, Vencel Somai, Felix Kreis, Flaviu Bulat, Alan J Wright, Kevin M Brindle
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 12 (03 23 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 33727417 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 the Author(s). Published by PNAS.

Chemical References

• Biomarkers
• Fumarates
• Deuterium

Topics

• Animals
• Biomarkers
• Cell Death
• Cell Line, Tumor
• Deuterium
• Disease Models, Animal
• Fumarates (metabolism)
• Heterografts
• Humans
• Immunohistochemistry
• Magnetic Resonance Imaging (methods)
• Magnetic Resonance Spectroscopy (methods)
• Mice
• Molecular Imaging (methods)