31P Nuclear Magnetic Resonance Measurements of ATPase Kinetics in Malignant Tumors

  • P. Okunieff
  • P. Vaupel
  • L. J. Neuringer
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 248)


The estimation of tumor growth rate is generally made on the basis of tumor histology, its site of origin, and sequential radiographic or caliper measurements of its dimensions. There are currently no techniques capable of measuring the expected growth rate non-invasively, serially and prospectively. An assay, able to measure the growth rate of a partially or fully treated tumor would be of obvious potential advantage for optimizing therapy. We propose the use of 31P nuclear magnetic resonance (NMR) magnetization transfer techniques for non-invasive and continuous estimation of tumor growth kinetics. Specifically, the rate of nucleoside triphosphate (NTP) synthesis can be quantitatively measured in vivo using 31P-NMR (1–4), and thus it is possible to accurately measure the metabolic rate of a tumor. Since higher energy consumption rates in tumors are likely to correlate with more rapid proliferation and growth (5–9), 31P magnetization transfer NMR should give an indirect indication of tumor growth rate. The purpose of this study was to examine the potential for 31P-NMR magnetization transfer experiments, measuring the kinetics of the reactions catalyzed by ATPase and creatine kinase to indirectly detect the decrease in growth rate which occurs in tumors of larger size.


Nuclear Magnetic Resonance Nuclear Magnetic Resonance Spectroscopy Magnetization Transfer Tumor Growth Rate Interpulse Interval 
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  1. 1.
    J.R. Alger, J.A. Hollander, and R.G. Shulman, in vivo phosphorus-31 nuclear magnetic resonance saturation transfer studies of adenosine-triphosphatase kinetics in Saccharomyces cerevisiae, Biochemistry. 21:2957 (1982).PubMedCrossRefGoogle Scholar
  2. 2.
    J.R. Alger, and R.G. Shulman, NMR studies of enzymatic rates in vitro and in vivo by magnetization transfer, Q. Rev. Biophys. 17:83 (1984).PubMedCrossRefGoogle Scholar
  3. 3.
    B.M. Hitzig, J.W. Prichard, H.L. Kantor, W.R. Ellington, J.S. Ingwall, C.T. Burt, S.I. Helman, and J. Koutcher, NMR spectroscopy as an investigative technique in physiology. FASEB J. 1:22 (1987).PubMedGoogle Scholar
  4. 4.
    J.J. Led, and H. Gesmar, The applicability of the magnetization transfer NMR technique to determine chemical exchange rates in extreme cases. The importance of complementary cases, J. Magn. Reson. 49:444 (1982).Google Scholar
  5. 5.
    P. Okunieff, J. Ramsay, T. Tokuhiro, B.M. Hitzig, E. Rummeny, L.J. Neuringer, and H.D. Suit, Estimation of tumor oxygen and metabolic rate using 31P MRS: Correlation of spin-lattice relaxation with tumor growth rate and DNA synthesis, Int. J. Radiat. Oncol. Biol. Phys. 14:1185 (1988).PubMedCrossRefGoogle Scholar
  6. 6.
    J.P. Freyer, E. Tustanoff, A.J. Franko, and R.M. Sutherland, In situ oxygen consumption rates of cells in V-79 multicellular spheroids during growth, J. Cell. Physiol. 118:53 (1984).PubMedCrossRefGoogle Scholar
  7. 7.
    G.D. Chiro, J. Hatazawa, D.A. Katz, H.V. Rizzoli, and D.J. De Michèle, Glucose utilization by intracranial meningiomas as an index of tumor aggres-sivity and probability of recurrence: A PET study, Radiology. 164:521 (1987).PubMedGoogle Scholar
  8. 8.
    R. Sutherland, J. Freyer, W. Mueller-Klieser, R. Wilson, C. Heacock, J. Sciandra, and B. Sordat, Cellular growth and metabolic adaptations to nutrient stress environments in tumor microregions, Int. J. Radiat. Oncol. Biol. Phys. 12:611 (1986).PubMedCrossRefGoogle Scholar
  9. 9.
    E.A. Newsholme, B. Crabtree and M.S.M Ardawi M.S.M., The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells, Bioscience Rep., 5:393 (1985).CrossRefGoogle Scholar
  10. 10.
    R.S. Sedlacek, R.P. Orcutt, H.D. Suit, and E.F. Rose, A flexible barrier at cage level for existing colonies: Production and maintenance of a limited stable anaerobic flora in a closed inbred mouse colony, in: “Recent Advances in Germfree Research,” S. Sasaki, A. Ozawa, and K. Hashimoto, eds., Tokai University Press, Tokyo (1981).Google Scholar
  11. 11.
    L. Revesz, Effect of tumour cells killed by X-rays upon the growth of admixed viable cells, Nature. 178:1391 (1956).PubMedCrossRefGoogle Scholar
  12. 12.
    M. Urano, and J. Kahn, Some practical questions in the tumor regrowth assay, in: “Rodent Tumor Models in Experimental Cancer Therapy,” R.F. Kallman, ed., Pergamon Press, New York (1987).Google Scholar
  13. 13.
    L. Norton, Cell kinetics in normal tissues and in tumors, in: “Cancer in the Young,” A.S. Levine, ed., Masson, New York (1982).Google Scholar
  14. 14.
    P. Okunieff, E. McFarland, E. Rummeny, C. Willett, B.M. Hitzig, L.J. Neuringer, and H. Suit, Effects of oxygen on the metabolism of murine tumors using in-vivo phosphorus-31 NMR, Am. J. Clin. Oncol. 10:475 (1987).PubMedCrossRefGoogle Scholar
  15. 15.
    P. Okunieff, F. Kallinowski, P. Vaupel, and L.J. Neuringer, Effect of hydralazine-induced vasodilation on the energy metabolism of murine tumors studied by in-vivo 31P-nuclear magnetic resonance spectroscopy, J. Natl. Cancer Inst. 80:745 (1988).PubMedCrossRefGoogle Scholar
  16. 16.
    P. Okunieff, J.A. Koutcher, L. Gerweck, E. McFarland, M. Urano, M., B.M. Hitzig, L. Neuringer, and H.D. Suit, Tumor size dependent metabolic changes in a murine fibrosarcoma: use of Fourier transform 3lP NMR to evaluate tumor energy metabolism, Int. J. Radiat. Oncol. Biol. Phys. 12:793 (1986).PubMedCrossRefGoogle Scholar
  17. 17.
    P. Okunieff, J.A. Koutcher, and H.D. Suit, Critical Review: Tumor size dependent metabolic changes in a murine fibrosarcoma: use of Fourier transform 3lP NMR to evaluate tumor energy metabolism, Invest. Radiol. 22:618 (1987).CrossRefGoogle Scholar
  18. 18.
    J. Ramsey, Personal communication (1988).Google Scholar
  19. 19.
    J.S. Cohen, R.C. Lyon, C. Chen, P.J. Faustino, G. Batist, M. Shoemaker, E. Rubalcaba, and K.H. Cowan, Differences in phosphate metabolite levels in drug-sensitive and-resistant human breast cancer cell lines determined by 31P magnetic resonance spectroscopy, Cancer Res. 46: 4087–4090 (1986).PubMedGoogle Scholar
  20. 20.
    J.J.H. Ackerman, T.K. Grove, G.G. Wong, D.G. Gadian, and G.K. Radda, Mapping of metabolites in whole animals by 31P NMR, Nature 283: 167 (1980)PubMedCrossRefGoogle Scholar
  21. 21.
    W.T. Evanochko, T.T. Sakai, T.C. Ng, R. Krishna, H.D. Kim, R.B. Zeidler, V.K. Ghanta, R.W. Brockman, L.M. Schiffer, P.G. Braunschweiger, and J.D. Glickson, NMR study of in vivo RIF-1 tumors: Analysis of perchloric acid extracts and identification of 1H, 31P, and 13C resonances, Biochim. Biophys. Acta. 805:104 (1984).PubMedCrossRefGoogle Scholar
  22. 22.
    P.F. Daly, R.C. Lyon, E.J. Straka, and J.S. Cohen, 31P-NMR spectroscopy of human cancer cells proliferating in a basement membrane gel. FASEB J. 2: 2596 (1988)PubMedGoogle Scholar
  23. 23.
    R. Freeman, and H.D. Hill, Fourier transform study of NMR spin-lattice relaxation by “progressive saturation”, J. Chem. Phys. 54:3367 (1971).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • P. Okunieff
    • 1
  • P. Vaupel
    • 1
  • L. J. Neuringer
    • 2
  1. 1.Dept. Radiation Medicine, Massachusetts General Hospital, Cancer CenterHarvard Medical SchoolBostonUSA
  2. 2.Francis Bitter National Magnet LaboratoryMassachusetts Institute of TechnologyCambridgeUSA

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