Hyperpolarized [1-13C]Dehydroascorbate MR Spectroscopy in a Murine Model of Prostate Cancer: Comparison with 18F-FDG PET

Journal of Nuclear Medicine

David M. Wilson¹  Kayvan R. Keshari¹  Victor Sai¹  John Kurhanewicz¹  Henry F. VanBrocklin¹  Zhen J. Wang¹ 

[1] Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California

关键词: hyperpolarized;    ascorbate;    redox;    positron emission tomography;    FDG;   

DOI  :  10.2967/jnumed.112.115402

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

Reduction and oxidation (redox) chemistry is increasingly implicated in cancer pathogenesis. To interrogate the redox status of prostate tumors noninvasively, we developed hyperpolarized [1-13C]dehydroascorbate (13C-DHA), the oxidized form of vitamin C, as an MR probe. In a model of transgenic adenocarcinoma of the mouse prostate (TRAMP), increased reduction of hyperpolarized 13C-DHA to vitamin C was observed in tumor, as compared with normal prostate and surrounding benign tissue. We hypothesized that this difference was due to higher concentrations of glutathione and increased transport of hyperpolarized 13C-DHA via the glucose transporters (GLUT1, GLUT3, and GLUT4) in TRAMP tumor. To test these hypotheses, hyperpolarized 13C-DHA MR spectroscopy (MRS) and 18F-FDG PET were applied as complementary technologies in the TRAMP model. Methods: Late-stage TRAMP tumors (>4 cm3) were studied at similar time points (MR studies conducted < 24 h after PET) in fasting mice by 18F-FDG PET and hyperpolarized 13C-DHA MR imaging on a small-animal PET/CT scanner and a 1H/3C 3-T MR scanner. PET data were processed using open-source AMIDE software to compare the standardized uptake values of tumor with those of surrounding muscle, and 13C-DHA MRS data were processed using custom software to compare the metabolite ratios (vitamin C/[vitamin C + 13C-DHA]). After in vivo studies, the tumor glutathione concentrations were determined using a spectrophotometric assay, and thiol staining was performed using mercury orange. Real-time polymerase chain reaction was used to evaluate the relevant transporters GLUT1, GLUT3, and GLUT4 and vitamin C transporters SVCT1 and SVCT2. GLUT1 was also evaluated by immunohistochemistry. Results: The average metabolite ratio was 0.28 ± 0.02 in TRAMP tumor, versus 0.11 ± 0.02 in surrounding benign tissue (n = 4), representing a 2.5-fold difference. The corresponding tumor-to-nontumor 18F-FDG uptake ratio was 3.0. The total glutathione was 5.1 ± 0.4 mM in tumor and 1.0 ± 0.2 mM in normal prostate, whereas reduced glutathione was 2.0 ± 0.3 mM and 0.8 ± 0.3 mM, respectively, corresponding to a 2.5-fold difference. In TRAMP tumor, mercury orange staining demonstrated increased thiols. Real-time polymerase chain reaction showed no significant difference in GLUT1 messenger RNA between TRAMP tumor and normal prostate, with immunohistochemistry (anti-GLUT1) also showing comparable staining. Conclusion: Both hyperpolarized 13C-DHA and 18F-FDG provide similar tumor contrast in the TRAMP model. Our findings suggest that the mechanism of in vivo hyperpolarized 13C-DHA reduction and the resulting tumor contrast correlates most strongly with glutathione concentration. In the TRAMP model, GLUT1 is not significantly upregulated and is unlikely to account for the contrast obtained using hyperpolarized 13C-DHA or 18F-FDG.

【 授权许可】

Unknown