Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy

An Erratum to this article was published on 01 December 2007

This article has been updated


Measurements of early tumor responses to therapy have been shown, in some cases, to predict treatment outcome. We show in lymphoma-bearing mice injected intravenously with hyperpolarized [1-13C]pyruvate that the lactate dehydrogenase–catalyzed flux of 13C label between the carboxyl groups of pyruvate and lactate in the tumor can be measured using 13C magnetic resonance spectroscopy and spectroscopic imaging, and that this flux is inhibited within 24 h of chemotherapy. The reduction in the measured flux after drug treatment and the induction of tumor cell death can be explained by loss of the coenzyme NAD(H) and decreases in concentrations of lactate and enzyme in the tumors. The technique could provide a new way to assess tumor responses to treatment in the clinic.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Flux of hyperpolarized 13C label between pyruvate and lactate in an EL-4 cell suspension.
Figure 2: Effect of addition of exogenous lactate and induction of cell death on flux of hyperpolarized 13C label between pyruvate and lactate in an EL-4 cell suspension.
Figure 3: Induction of cell death depletes EL-4 cells of NAD(H).
Figure 4: Flux of hyperpolarized 13C label between pyruvate and lactate in EL-4 tumors.
Figure 5: 13C spectroscopic imaging of EL-4 tumors before and after drug treatment.

Change history

  • 12 November 2007

    In the version of this article initially published, Equation 2 was incorrect. Additionally, peak 1 in Figure 1a was incorrectly defined in the figure legend. The errors have been corrected in the HTML and PDF versions of the article.


  1. Neves, A.A. & Brindle, K.M. Assessing responses to cancer therapy using molecular imaging. Biochim. Biophys. Acta 1766, 242–261 (2006).

    CAS  PubMed  Google Scholar 

  2. Czernin, J., Weber, W.A. & Herschman, H.R. Molecular imaging in the development of cancer therapeutics. Annu. Rev. Med. 57, 99–118 (2006).

    Article  CAS  Google Scholar 

  3. Weber, W.A. Positron emission tomography as an imaging biomarker. J. Clin. Oncol. 24, 3282–3292 (2006).

    Article  CAS  Google Scholar 

  4. Stroobants, S. et al. (18)FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur. J. Cancer 39, 2012–2020 (2003).

    Article  CAS  Google Scholar 

  5. Kettunen, M.I. & Brindle, K.M. Apoptosis detection using magnetic resonance imaging and spectroscopy. Prog. Nucl. Magn. Reson. Spectrosc. 47, 175–185 (2005).

    Article  CAS  Google Scholar 

  6. Ross, B.D. et al. Evaluation of cancer therapy using diffusion magnetic resonance imaging. Mol. Cancer Ther. 2, 581–587 (2003).

    CAS  PubMed  Google Scholar 

  7. Moffat, B.A. et al. Functional diffusion map: A noninvasive MRI biomarker for early stratification of clinical brain tumor response. Proc. Natl. Acad. Sci. USA 102, 5524–5529 (2005).

    Article  CAS  Google Scholar 

  8. Shulman, R.G. et al. Cellular applications of 31P and 13C nuclear magnetic resonance. Science 205, 160–166 (1979).

    Article  CAS  Google Scholar 

  9. Ardenkjaer-Larsen, J.H. et al. Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR. Proc. Natl. Acad. Sci. USA 100, 10158–10163 (2003).

    Article  CAS  Google Scholar 

  10. Golman, K., Ardenkjær-Larsen, J.H., Petersson, J.S., Månsson, S. & Leunbach, I. Molecular imaging with endogenous substances. Proc. Natl. Acad. Sci. USA 100, 10435–10439 (2003).

    Article  CAS  Google Scholar 

  11. Golman, K., in 't Zandt, R. & Thaning, M. Real-time metabolic imaging. Proc. Natl. Acad. Sci. USA 103, 11270–11275 (2006).

    Article  CAS  Google Scholar 

  12. Golman, K. & Petersson, J.S. Metabolic imaging and other applications of hyperpolarized 13C. Acad. Radiol. 13, 932–942 (2006).

    Article  Google Scholar 

  13. Golman, K., Zandt, R.I., Lerche, M., Pehrson, R. & Ardenkjaer-Larsen, J.H. Metabolic imaging by hyperpolarized 13C magnetic resonance imaging for in vivo tumor diagnosis. Cancer Res. 66, 10855–10860 (2006).

    Article  CAS  Google Scholar 

  14. Brindle, K.M. NMR methods for measuring enzyme kinetics in vivo. Prog. Nucl. Magn. Reson. Spectrosc. 20, 257–293 (1988).

    Article  CAS  Google Scholar 

  15. Brindle, K.M., Campbell, I.D. & Simpson, R.J. A 1H-NMR study of the activity expressed by lactate dehydrogenase in the human erythrocyte. Eur. J. Biochem. 158, 299–305 (1986).

    Article  CAS  Google Scholar 

  16. Schmitz, J.E., Kettunen, M.I., Hu, D.E. & Brindle, K.M. 1H MRS-visible lipids accumulate during apoptosis of lymphoma cells in vitro and in vivo. Magn. Reson. Med. 54, 43–50 (2005).

    Article  CAS  Google Scholar 

  17. Poot, M. & Pierce, R.H. Detection of changes in mitochondrial function during apoptosis by simultaneous staining with multiple fluorescent dyes and correlated multiparameter flow cytometry. Cytometry 35, 311–317 (1999).

    Article  CAS  Google Scholar 

  18. Sims, J.L., Berger, S.J. & Berger, N.A. Poly(ADP-ribose) polymerase inhibitors preserve nicotinamide adenine dinucleotide and adenosine 5′-triphosphate pools in DNA-damaged cells: mechanism of stimulation of unscheduled DNA synthesis. Biochemistry 22, 5188–5194 (1983).

    Article  CAS  Google Scholar 

  19. Williams, S.N.O., Anthony, M.L. & Brindle, K.M. Induction of apoptosis in two mammalian cell lines results in increased levels of fructose-1,6-bisphosphate and CDP-choline as determined by 31P MRS. Magn. Reson. Med. 40, 411–420 (1998).

    Article  CAS  Google Scholar 

  20. Filipovic, D.M., Meng, X. & Reeves, W.B. Inhibition of PARP prevents oxidant-induced necrosis but not apoptosis in LLC-PK1 cells. Am. J. Physiol. 277, F428–F436 (1999).

    CAS  PubMed  Google Scholar 

  21. Aboagye, E.O., Bhujwalla, Z.M., Shungu, D.C. & Glickson, J.D. Detection of tumour response to chemotherapy by 1H nuclear magnetic resonance spectroscopy: Effect of 5-fluorouracil on lactate levels in radiation-induced fibrosarcoma I tumours. Cancer Res. 58, 1063–1067 (1998).

    CAS  PubMed  Google Scholar 

  22. Poptani, H. et al. Detecting early response to cyclophosphamide treatment of RIF-1 tumors using selective multiple quantum spectroscopy (SelMQC) and dynamic contrast enhanced imaging. NMR Biomed. 16, 102–111 (2003).

    Article  CAS  Google Scholar 

  23. Hakumaki, J.M., Poptani, H., Sandmair, A-M., Yla-Herttuala, S. & Kauppinen, R.A. 1H MRS detects polyunsaturated fatty acid accumulation during gene therapy of glioma: Implications for the in vivo detection of apoptosis. Nat. Med. 5, 1323–1327 (1999).

    Article  CAS  Google Scholar 

  24. Anthony, M.L., Zhao, M. & Brindle, K.M. Inhibition of phosphatidylcholine biosynthesis following induction of apoptosis in HL-60 cells. J. Biol. Chem. 274, 19686–19692 (1999).

    Article  CAS  Google Scholar 

  25. Zhao, M., Beauregard, D.A., Loizou, L., Davletov, B. & Brindle, K.M. Non-invasive detection of apoptosis using magnetic resonance imaging and a targeted contrast agent. Nat. Med. 7, 1241–1244 (2001).

    Article  CAS  Google Scholar 

  26. Vassault, A. Lactate dehydrogenase. in Methods of Enzymatic Analysis Vol. 3 (ed. Bergmeyer, H.U.) 118–126 (Verlag Chemie, Deerfield Beach, Florida, 1983).

    CAS  Google Scholar 

Download references


F.A.G. received a Cancer Research UK and Royal College of Radiologists (UK) clinical research training fellowship, and S.E.D. received a US National Institutes of Health–Cambridge studentship. This work was supported by a Cancer Research UK programme grant to K.M.B. (C197/A3514). The polarizer and related materials were provided by GE Healthcare.

Author information

Authors and Affiliations



S.E.D. conducted the cell experiments and operated the polarizer with F.A.G. M.I.K. was responsible for MRS and imaging experiments. S.E.D., F.A.G. and M.I.K. were jointly responsible for data analysis. D.-E.H. was responsible for tumor implantation and animal handling during the MRS experiments. M.L., J.W., K.G. and J.H.A.-L. provided advice and assistance with the pyruvate preparation and operation of the polarizer. K.M.B. organized the study, devised the kinetics analysis and wrote the paper.

Corresponding author

Correspondence to Kevin M Brindle.

Ethics declarations

Competing interests

The hyperpolarizer is on loan from GE Healthcare and is the subject of a research agreement between the University of Cambridge and GE Healthcare. GE Healthcare also supplied the 13C-labeled pyruvate and the trityl radical used in the hyperpolarization process.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–5, Supplementary Data, and Supplementary Methods (PDF 684 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Day, S., Kettunen, M., Gallagher, F. et al. Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy. Nat Med 13, 1382–1387 (2007).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing