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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2004 Jun 29;359(1446):987–996. doi: 10.1098/rstb.2003.1376

Current issues in the utility of 19F nuclear magnetic resonance methodologies for the assessment of tumour hypoxia.

Simon P Robinson 1, John R Griffiths 1
PMCID: PMC1693379  PMID: 15306411

Abstract

It is now well established that uncontrolled proliferation of tumour cells together with the chaotic and poorly regulated blood supply of solid tumours result in tissue hypoxia, and that hypoxic regions of tumours are resistant to radiotherapy and chemotherapy. The development and application of non-invasive methods to rapidly determine the degree and extent of tumour hypoxia in an individual tumour would clearly enhance cancer treatment strategies. This review describes the current status of two (19)F nuclear magnetic resonance (NMR) methodologies that have been exploited to investigate tumour hypoxia, namely: (i) (19)F NMR oximetry following administration of perfluorocarbons, from which tumour p(O)(2) measurements can be made; and (ii) (19)F NMR measurements of the tumour retention of fluorinated 2-nitroimidazoles.

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Selected References

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  1. Aboagye E. O., Maxwell R. J., Horsman M. R., Lewis A. D., Workman P., Tracy M., Griffiths J. R. The relationship between tumour oxygenation determined by oxygen electrode measurements and magnetic resonance spectroscopy of the fluorinated 2-nitroimidazole SR-4554. Br J Cancer. 1998;77(1):65–70. doi: 10.1038/bjc.1998.10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aboagye E. O., Maxwell R. J., Kelson A. B., Tracy M., Lewis A. D., Graham M. A., Horsman M. R., Griffiths J. R., Workman P. Preclinical evaluation of the fluorinated 2-nitroimidazole N-(2-hydroxy-3,3,3-trifluoropropyl)-2-(2-nitro-1-imidazolyl) acetamide (SR-4554) as a probe for the measurement of tumor hypoxia. Cancer Res. 1997 Aug 1;57(15):3314–3318. [PubMed] [Google Scholar]
  3. Adam M. F., Dorie M. J., Brown J. M. Oxygen tension measurements of tumors growing in mice. Int J Radiat Oncol Biol Phys. 1999 Aug 1;45(1):171–180. doi: 10.1016/s0360-3016(99)00157-1. [DOI] [PubMed] [Google Scholar]
  4. Baldwin N. J., Ng T. C. Oxygenation and metabolic status of KHT tumors as measured simultaneously by 19F magnetic resonance imaging and 31P magnetic resonance spectroscopy. Magn Reson Imaging. 1996;14(5):541–551. doi: 10.1016/0730-725x(96)00049-5. [DOI] [PubMed] [Google Scholar]
  5. Brizel D. M., Rosner G. L., Harrelson J., Prosnitz L. R., Dewhirst M. W. Pretreatment oxygenation profiles of human soft tissue sarcomas. Int J Radiat Oncol Biol Phys. 1994 Oct 15;30(3):635–642. doi: 10.1016/0360-3016(92)90950-m. [DOI] [PubMed] [Google Scholar]
  6. Brizel D. M., Scully S. P., Harrelson J. M., Layfield L. J., Bean J. M., Prosnitz L. R., Dewhirst M. W. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 1996 Mar 1;56(5):941–943. [PubMed] [Google Scholar]
  7. Brizel D. M., Sibley G. S., Prosnitz L. R., Scher R. L., Dewhirst M. W. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 1997 May 1;38(2):285–289. doi: 10.1016/s0360-3016(97)00101-6. [DOI] [PubMed] [Google Scholar]
  8. Chaplin D. J., Horsman M. R., Aoki D. S. Nicotinamide, Fluosol DA and Carbogen: a strategy to reoxygenate acutely and chronically hypoxic cells in vivo. Br J Cancer. 1991 Jan;63(1):109–113. doi: 10.1038/bjc.1991.22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dardzinski B. J., Sotak C. H. Rapid tissue oxygen tension mapping using 19F inversion-recovery echo-planar imaging of perfluoro-15-crown-5-ether. Magn Reson Med. 1994 Jul;32(1):88–97. doi: 10.1002/mrm.1910320112. [DOI] [PubMed] [Google Scholar]
  10. Evans S. M., Bergeron M., Ferriero D. M., Sharp F. R., Hermeking H., Kitsis R. N., Geenen D. L., Bialik S., Lord E. M., Koch C. J. Imaging hypoxia in diseased tissues. Adv Exp Med Biol. 1997;428:595–603. doi: 10.1007/978-1-4615-5399-1_84. [DOI] [PubMed] [Google Scholar]
  11. Fan Xiaobing, River Jonathan N., Zamora Marta, Al-Hallaq Hania A., Karczmar Gregory S. Effect of carbogen on tumor oxygenation: combined fluorine-19 and proton MRI measurements. Int J Radiat Oncol Biol Phys. 2002 Nov 15;54(4):1202–1209. doi: 10.1016/s0360-3016(02)03035-3. [DOI] [PubMed] [Google Scholar]
  12. Fyles A. W., Milosevic M., Wong R., Kavanagh M. C., Pintilie M., Sun A., Chapman W., Levin W., Manchul L., Keane T. J. Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol. 1998 Aug;48(2):149–156. doi: 10.1016/s0167-8140(98)00044-9. [DOI] [PubMed] [Google Scholar]
  13. Harris Adrian L. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer. 2002 Jan;2(1):38–47. doi: 10.1038/nrc704. [DOI] [PubMed] [Google Scholar]
  14. Hees P. S., Sotak C. H. Assessment of changes in murine tumor oxygenation in response to nicotinamide using 19F NMR relaxometry of a perfluorocarbon emulsion. Magn Reson Med. 1993 Mar;29(3):303–310. doi: 10.1002/mrm.1910290305. [DOI] [PubMed] [Google Scholar]
  15. Hockel M., Schlenger K., Aral B., Mitze M., Schaffer U., Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 1996 Oct 1;56(19):4509–4515. [PubMed] [Google Scholar]
  16. Horsman M. R. Measurement of tumor oxygenation. Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):701–704. doi: 10.1016/s0360-3016(98)00332-0. [DOI] [PubMed] [Google Scholar]
  17. Hunjan S., Mason R. P., Constantinescu A., Peschke P., Hahn E. W., Antich P. P. Regional tumor oximetry: 19F NMR spectroscopy of hexafluorobenzene. Int J Radiat Oncol Biol Phys. 1998 Apr 1;41(1):161–171. doi: 10.1016/s0360-3016(98)00020-0. [DOI] [PubMed] [Google Scholar]
  18. Hunjan S., Zhao D., Constantinescu A., Hahn E. W., Antich P. P., Mason R. P. Tumor oximetry: demonstration of an enhanced dynamic mapping procedure using fluorine-19 echo planar magnetic resonance imaging in the Dunning prostate R3327-AT1 rat tumor. Int J Radiat Oncol Biol Phys. 2001 Mar 15;49(4):1097–1108. doi: 10.1016/s0360-3016(00)01460-7. [DOI] [PubMed] [Google Scholar]
  19. Höckel M., Schlenger K., Knoop C., Vaupel P. Oxygenation of carcinomas of the uterine cervix: evaluation by computerized O2 tension measurements. Cancer Res. 1991 Nov 15;51(22):6098–6102. [PubMed] [Google Scholar]
  20. Jin G. Y., Li S. J., Moulder J. E., Raleigh J. A. Dynamic measurements of hexafluoromisonidazole (CCI-103F) retention in mouse tumours by 1H/19F magnetic resonance spectroscopy. Int J Radiat Biol. 1990 Dec;58(6):1025–1034. doi: 10.1080/09553009014552331. [DOI] [PubMed] [Google Scholar]
  21. Joseph P., Jaiswal A. K., Stobbe C. C., Chapman J. D. The role of specific reductases in the intracellular activation and binding of 2-nitroimidazoles. Int J Radiat Oncol Biol Phys. 1994 May 15;29(2):351–355. doi: 10.1016/0360-3016(94)90288-7. [DOI] [PubMed] [Google Scholar]
  22. Kaanders Johannes H. A. M., Pop Lucas A. M., Marres Henri A. M., Bruaset Ingolv, van den Hoogen Franciscus J. A., Merkx Matthijs A. W., van der Kogel Albert J. ARCON: experience in 215 patients with advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2002 Mar 1;52(3):769–778. doi: 10.1016/s0360-3016(01)02678-5. [DOI] [PubMed] [Google Scholar]
  23. Kaanders Johannes H. A. M., Wijffels Karien I. E. M., Marres Henri A. M., Ljungkvist Anna S. E., Pop Lucas A. M., van den Hoogen Franciscus J. A., de Wilde Peter C. M., Bussink Johan, Raleigh James A., van der Kogel Albert J. Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Cancer Res. 2002 Dec 1;62(23):7066–7074. [PubMed] [Google Scholar]
  24. Kwock L., Gill M., McMurry H. L., Beckman W., Raleigh J. A., Joseph A. P. Evaluation of a fluorinated 2-nitroimidazole binding to hypoxic cells in tumor-bearing rats by 19F magnetic resonance spectroscopy and immunohistochemistry. Radiat Res. 1992 Jan;129(1):71–78. [PubMed] [Google Scholar]
  25. Le D., Mason R. P., Hunjan S., Constantinescu A., Barker B. R., Antich P. P. Regional tumor oxygen dynamics: 19F PBSR EPI of hexafluorobenzene. Magn Reson Imaging. 1997;15(8):971–981. doi: 10.1016/s0730-725x(97)00035-0. [DOI] [PubMed] [Google Scholar]
  26. Li S. J., Jin G. Y., Moulder J. E. Prediction of tumor radiosensitivity by hexafluoromisonidazole retention monitored by [1H]/[19F] magnetic resonance spectroscopy. Cancer Commun. 1991 May;3(5):133–139. doi: 10.3727/095535491820873353. [DOI] [PubMed] [Google Scholar]
  27. Lord E. M., Harwell L., Koch C. J. Detection of hypoxic cells by monoclonal antibody recognizing 2-nitroimidazole adducts. Cancer Res. 1993 Dec 1;53(23):5721–5726. [PubMed] [Google Scholar]
  28. Lutz J., Nöth U., Morrissey S. P., Adolf H., Deichmann R., Haase A. Measurement of oxygen tensions in the abdominal cavity and in the skeletal muscle using 19F-MRI of neat PFC droplets. Adv Exp Med Biol. 1997;428:569–572. doi: 10.1007/978-1-4615-5399-1_80. [DOI] [PubMed] [Google Scholar]
  29. Mason R. P., Antich P. P., Babcock E. E., Constantinescu A., Peschke P., Hahn E. W. Non-invasive determination of tumor oxygen tension and local variation with growth. Int J Radiat Oncol Biol Phys. 1994 Apr 30;29(1):95–103. doi: 10.1016/0360-3016(94)90231-3. [DOI] [PubMed] [Google Scholar]
  30. Mason R. P., Constantinescu A., Hunjan S., Le D., Hahn E. W., Antich P. P., Blum C., Peschke P. Regional tumor oxygenation and measurement of dynamic changes. Radiat Res. 1999 Sep;152(3):239–249. [PubMed] [Google Scholar]
  31. Mason R. P., Hunjan S., Le D., Constantinescu A., Barker B. R., Wong P. S., Peschke P., Hahn E. W., Antich P. P. Regional tumor oxygen tension: fluorine echo planar imaging of hexafluorobenzene reveals heterogeneity of dynamics. Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):747–750. doi: 10.1016/s0360-3016(98)00306-x. [DOI] [PubMed] [Google Scholar]
  32. Mason R. P., Rodbumrung W., Antich P. P. Hexafluorobenzene: a sensitive 19F NMR indicator of tumor oxygenation. NMR Biomed. 1996 May;9(3):125–134. doi: 10.1002/(SICI)1099-1492(199605)9:3<125::AID-NBM405>3.0.CO;2-F. [DOI] [PubMed] [Google Scholar]
  33. Maxwell R. J., Workman P., Griffiths J. R. Demonstration of tumor-selective retention of fluorinated nitroimidazole probes by 19F magnetic resonance spectroscopy in vivo. Int J Radiat Oncol Biol Phys. 1989 Apr;16(4):925–929. doi: 10.1016/0360-3016(89)90888-2. [DOI] [PubMed] [Google Scholar]
  34. Nordsmark M., Loncaster J., Chou S. C., Havsteen H., Lindegaard J. C., Davidson S. E., Varia M., West C., Hunter R., Overgaard J. Invasive oxygen measurements and pimonidazole labeling in human cervix carcinoma. Int J Radiat Oncol Biol Phys. 2001 Feb 1;49(2):581–586. doi: 10.1016/s0360-3016(00)01493-0. [DOI] [PubMed] [Google Scholar]
  35. Nordsmark M., Overgaard M., Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol. 1996 Oct;41(1):31–39. doi: 10.1016/s0167-8140(96)91811-3. [DOI] [PubMed] [Google Scholar]
  36. Raleigh J. A., Chou S. C., Arteel G. E., Horsman M. R. Comparisons among pimonidazole binding, oxygen electrode measurements, and radiation response in C3H mouse tumors. Radiat Res. 1999 May;151(5):580–589. [PubMed] [Google Scholar]
  37. Raleigh J. A., Chou S. C., Tables L., Suchindran S., Varia M. A., Horsman M. R. Relationship of hypoxia to metallothionein expression in murine tumors. Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):727–730. doi: 10.1016/s0360-3016(98)00329-0. [DOI] [PubMed] [Google Scholar]
  38. Raleigh J. A., Franko A. J., Kelly D. A., Trimble L. A., Allen P. S. Development of an in vivo 19F magnetic resonance method for measuring oxygen deficiency in tumors. Magn Reson Med. 1991 Dec;22(2):451–466. doi: 10.1002/mrm.1910220253. [DOI] [PubMed] [Google Scholar]
  39. Raleigh J. A., Franko A. J., Treiber E. O., Lunt J. A., Allen P. S. Covalent binding of a fluorinated 2-nitroimidazole to EMT-6 tumors in Balb/C mice: detection by F-19 nuclear magnetic resonance at 2.35 T. Int J Radiat Oncol Biol Phys. 1986 Jul;12(7):1243–1245. doi: 10.1016/0360-3016(86)90268-3. [DOI] [PubMed] [Google Scholar]
  40. Robinson S. P., Collingridge D. R., Howe F. A., Rodrigues L. M., Chaplin D. J., Griffiths J. R. Tumour response to hypercapnia and hyperoxia monitored by FLOOD magnetic resonance imaging. NMR Biomed. 1999 Apr;12(2):98–106. doi: 10.1002/(sici)1099-1492(199904)12:2<98::aid-nbm556>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  41. Robinson S. P., Howe F. A., Rodrigues L. M., Stubbs M., Griffiths J. R. Magnetic resonance imaging techniques for monitoring changes in tumor oxygenation and blood flow. Semin Radiat Oncol. 1998 Jul;8(3):197–207. doi: 10.1016/s1053-4296(98)80045-3. [DOI] [PubMed] [Google Scholar]
  42. Rojas A. Radiosensitization with normobaric oxygen and carbogen. Radiother Oncol. 1991;20 (Suppl 1):65–70. doi: 10.1016/0167-8140(91)90190-r. [DOI] [PubMed] [Google Scholar]
  43. Secomb T. W., Hsu R., Ong E. T., Gross J. F., Dewhirst M. W. Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors. Acta Oncol. 1995;34(3):313–316. doi: 10.3109/02841869509093981. [DOI] [PubMed] [Google Scholar]
  44. Seddon Beatrice M., Maxwell Ross J., Honess Davina J., Grimshaw Rachel, Raynaud Florence, Tozer Gillian M., Workman Paul. Validation of the fluorinated 2-nitroimidazole SR-4554 as a noninvasive hypoxia marker detected by magnetic resonance spectroscopy. Clin Cancer Res. 2002 Jul;8(7):2323–2335. [PubMed] [Google Scholar]
  45. Seddon Beatrice M., Payne Geoffrey S., Simmons Laura, Ruddle Ruth, Grimshaw Rachel, Tan Siew, Turner Alison, Raynaud Florence, Halbert Gavin, Leach Martin O. A phase I study of SR-4554 via intravenous administration for noninvasive investigation of tumor hypoxia by magnetic resonance spectroscopy in patients with malignancy. Clin Cancer Res. 2003 Nov 1;9(14):5101–5112. [PubMed] [Google Scholar]
  46. Snyder S. A., Lanzen J. L., Braun R. D., Rosner G., Secomb T. W., Biaglow J., Brizel D. M., Dewhirst M. W. Simultaneous administration of glucose and hyperoxic gas achieves greater improvement in tumor oxygenation than hyperoxic gas alone. Int J Radiat Oncol Biol Phys. 2001 Oct 1;51(2):494–506. doi: 10.1016/s0360-3016(01)01654-6. [DOI] [PubMed] [Google Scholar]
  47. Song Yulin, Constantinescu Anca, Mason Ralph P. Dynamic breast tumor oximetry: the development of prognostic radiology. Technol Cancer Res Treat. 2002 Dec;1(6):471–478. doi: 10.1177/153303460200100607. [DOI] [PubMed] [Google Scholar]
  48. Wang Z., Su M-Y, Nalcioglu O. Applications of dynamic contrast enhanced MRI in oncology: measurement of tumor oxygen tension. Technol Cancer Res Treat. 2002 Feb;1(1):29–38. doi: 10.1177/153303460200100104. [DOI] [PubMed] [Google Scholar]
  49. Workman P. Bioreductive mechanisms. Int J Radiat Oncol Biol Phys. 1992;22(4):631–637. doi: 10.1016/0360-3016(92)90493-2. [DOI] [PubMed] [Google Scholar]
  50. Workman P., Maxwell R. J., Griffiths J. R. Non-invasive MRS in new anticancer drug development. NMR Biomed. 1992 Sep-Oct;5(5):270–272. doi: 10.1002/nbm.1940050513. [DOI] [PubMed] [Google Scholar]
  51. Yeh K. A., Biade S., Lanciano R. M., Brown D. Q., Fenning M. C., Babb J. S., Hanks G. E., Chapman D. C. Polarographic needle electrode measurements of oxygen in rat prostate carcinomas: accuracy and reproducibility. Int J Radiat Oncol Biol Phys. 1995 Aug 30;33(1):111–118. doi: 10.1016/0360-3016(95)00036-x. [DOI] [PubMed] [Google Scholar]
  52. Zhao Dawen, Constantinescu Anca, Hahn Eric W., Mason Ralph P. Differential oxygen dynamics in two diverse Dunning prostate R3327 rat tumor sublines (MAT-Lu and HI) with respect to growth and respiratory challenge. Int J Radiat Oncol Biol Phys. 2002 Jul 1;53(3):744–756. doi: 10.1016/s0360-3016(02)02822-5. [DOI] [PubMed] [Google Scholar]
  53. van der Sanden B. P., Heerschap A., Simonetti A. W., Rijken P. F., Peters H. P., Stüben G., van der Kogel A. J. Characterization and validation of noninvasive oxygen tension measurements in human glioma xenografts by 19F-MR relaxometry. Int J Radiat Oncol Biol Phys. 1999 Jun 1;44(3):649–658. doi: 10.1016/s0360-3016(98)00555-0. [DOI] [PubMed] [Google Scholar]

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