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Oxygen Transport To Tissue XXIII pp 285–292Cite as

Non-Invasive PET and Spect Imaging of Tissue Hypoxia Using Isotopically Labeled 2-Nitroimidazoles

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 510))

Abstract

The measurement of pathologically low levels of tissue pO2 is an important diagnostic goal for determining the prognosis of many clinically important diseases including cardiovascular insufficiency, stroke and cancer. A class of bioreductively activated drugs, typified by the 2-nitroimidazoles, has excellent potential for application to this goal. Such drugs bind to cells at a rate which is maximal under conditions of severe hypoxia (e.g. less than 0.05% oxygen) and is inhibited, with Michaelis-Menten kinetics, as a function of increasing oxygen concentration. A number of detection possibilities exist for the drug adducts, including invasive assays which can measure drug adducts in tissue sections at cell-to-cell resolution. Use of such agents in noninvasive assays is important and, to this end, a number of drugs have been conjugated with radioactive isotopes suitable for detection by Nuclear Medicine techniques. In contrast with the invasive assays, resolution and contrast is much more limited with the non-invasive assays. Thus, there are many factors contributing to the balance of pros and cons for the non-invasive vs. invasive use of 2-nitroimidazole drugs as hypoxia detectors. These factors will be summarized in this review, with emphasis on compounds suitable for clinical use. PET (positron emission tomography) imaging with F-labeled EF5 (a drug in current clinical trials using invasive assays) will be described.

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References

  1. M. Hockel, C. Knoop, K. Schlenger, B. Vordran, E. Baussmann, M. Mitze, P. G. Knapstein, And P. Vaupel, Intratumor p02 predicts survival in advanced cancer of the uterine cervix. Radiotherapy and Oncology 26, 45–50 (1993).

    Article  PubMed  CAS  Google Scholar 

  2. D. M. Brizel, S. P. Scully, J. M. Harrelson, L. J. Layfield, J. M. Bean, L. R. Prosnitz, And M. W. Dewhirst, Tissue oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 56, 941–943 (1996).

    PubMed  CAS  Google Scholar 

  3. M. Nordsmark, M. Overgaard, And J. Overgaard, Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radioth. and Oncol. 41, 31–39 (1996).

    CAS  Google Scholar 

  4. A. W. Fyles, M. Milosevic, R. Wong, M. C. Kavanagh, M. Pintilie, W. Chapman, W. Levin, L. Manchul, T. J. Keane, and R. P. Hill, Oxygenation predicts radiation response and survival in patients with cervix cancer. Radioth. and Oncol. 48, 149–156 (1998).

    Article  CAS  Google Scholar 

  5. S. D. Young, R. S. Marshall, And R. P. Hill, Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proc. Nat. Acad. Sci. USA 85, 9533–9537 (1988).

    Article  PubMed  CAS  Google Scholar 

  6. T. G. Graeber, C. Osmanian, T. Jacks, D. E. Housman, C. J. Koch, S. W. Lowe, And A. J. Giaccia, Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379, 88–91 (1996).

    Article  PubMed  CAS  Google Scholar 

  7. T. Y. Reynolds, S. Rockwell, And P. M. Glazer, Genetic instability induced by the tumor microenvironment. Cancer Res. 56, 5754–5757 (1996).

    PubMed  CAS  Google Scholar 

  8. G. E. Adams, In: Selective Activation of Drugs by Redox Processes (Adams, G.E., Breccia, A., Fielden, E.M. and Wardman, P., eds). NATO Series A 198, Plenum Press, NY (1990).

    Google Scholar 

  9. C. J. Koch, S. M. Evans, And E. M. Lord, Oxygen dependence of cellular uptake of EF5 [2-(2nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoroproply)acetamide]: analysis of drug adducts by fluorescent antibodies vs bound radioactivity. Br. J. Cancer 72, 869–874 (1995).

    Article  PubMed  CAS  Google Scholar 

  10. C. J. Koch, C. C. Stobbe, And K. A. Baer, Metabolism induced binding of 14C -misonidazole to hypoxic cells: kinetic dependence on oxygen concentration and misonidazole concentration. Int. J. Radiat. Oncol. Biol. Phys. 10, 1327–1332 (1984).

    Article  PubMed  CAS  Google Scholar 

  11. C. J. Koch, Measurement of Absolute Oxygen Levels in Cells and Tissues using Oxygen Sensors and the 2-nitroimidazole EF5. Meth. Enzymol. - Antioxidants and Redox Cycling In Press (2002).

    Google Scholar 

  12. A. J. Varghese, S. Gulyas, And J. K. Mohindra, Hypoxia-dependent reduction of 1-(2-nitro1-imidazolyl)-3-methoxy-2-propanol by Chinese hamster ovary cells and KHT tumor cells in vitro and in vivo. Cancer Res. 36, 3761–3765 (1976).

    PubMed  CAS  Google Scholar 

  13. J. D. Chapman, K. A. Baer, And J. Lee, Characteristics of the metabolism-induced binding of misonidazole to hypoxic mammalian cells. Cancer Res. 43, 1523–1528 (1983).

    PubMed  CAS  Google Scholar 

  14. B. M. Garrecht, And J. D. Chapman, The labelling of EMT-6 tumors in Balb/c mice with 14C-misonidazole. Brit. J. Radiol. 56, 745–753 (1983).

    Article  CAS  Google Scholar 

  15. J. A. Raleigh, G. G. Miller, A. J. Franko, C. J. Koch, A. F. Fuciarelli, And D. A. Kelley, Fluorescence immunohistochemical detection of hypoxic cells in spheroids and tumours. Br. J. Cancer 56, 395–400 (1987).

    Article  PubMed  CAS  Google Scholar 

  16. R. J. Hodgkiss, G. Jones, A. Long, J. Parrick, K. A. Smith, And M. R. L. Stratford, Flow cytometric evaluation of hypoxic cells in solid experimental tumours using fluorescence immunodetection. Br. J. Cancer 63, 119–125 (1991).

    Article  PubMed  CAS  Google Scholar 

  17. E. M. Lord, L. W. Harwell, And C. J. Koch, Detection of hypoxic cells by monoclonal antibody recognizing 2-nitroimidazole adducts. Cancer Res. 53, 5271–5276 (1993).

    Google Scholar 

  18. A. S. Kennedy, J. A. Raleigh, G. M. Perez, D. P. Calkins, D. E. Thrall, D. B. Novotny, And M. Varia, Proliferation and hypoxia in human squamous cell carcinoma of the cervix: first report of combined immunohistochemical assays. Int. J. Radiat. Oncol. Biol. Phys. 37, 897–905 (1997).

    Article  PubMed  CAS  Google Scholar 

  19. K. I. Wijffels, J. H. Kaanders, P. F. Rijken, J. Bussink, F. J. Van Den Hoogen, H. A. Marres, P. C. De Wilde, J. A. Raleigh, And A. J. Van Der Kogel, Vascular architecture and hypoxic profiles in human head and neck squamous cell carcinomas. Brit. J. Cancer 83, 674–683 (2000).

    Article  CAS  Google Scholar 

  20. S. M. Evans, S. Hahn, D. R. Pook, W. T. Jenkins, A. A. Chalian, P. Zhang, C. Stevens, R. Weber, I. Benjamin, N. Mirza, M. Morgan, S. Rubin, W. G. Mckenna, E. M. Lord, And C. J. Koch, Detection of hypoxia in human squamous cell carcinoma by EF5 binding. Cancer Res. 60, 2018–2024 (2000).

    PubMed  CAS  Google Scholar 

  21. S. M. Evans, S. Hahn, D. R. Pook, P. J. Zhang, W. T. Jenkins, D. Fraker, R. A. Hsi, W. G. Mckenna, And C. J. Koch, Hypoxia in human intraperitoneal and extremity sarcomas. Int. J. Radiat. Oncol. Biol. Phys. 49, 587–596 (2000).

    Article  Google Scholar 

  22. W. T. Jenkins, S. M. Evans, And C. J. Koch, Hypoxia and necrosis in rat (L glioma and Morris 7777 hepatoma tumors: comparative measurements using EF5 binding and Eppendorf needle electrode. Int. J. Rad. Onc. Biol. Phys. 46, 1005–1017 (2000).

    Article  CAS  Google Scholar 

  23. M. C. Kavanagh, A. Sun, Q. Hu, And R. P. Hill, Comparing techniques of measuring tumor hypoxia in different murine tumors: Eppendorf pO2 histograph, [3H]misonidazole binding and paired survival assay. Radiat. Res. 145, 491–500 (1996).

    CAS  Google Scholar 

  24. M. I. Saunders, S. Dische, P. J. Anderson, And J. R. Flockhard, The neurotoxicity of misonidazole and its relationship to dose, half-life and concentration in the serum. Br. J. Cancer 37:, 268–270 (1978).

    Google Scholar 

  25. J. S. Rasey, K. A. Krohn, And S. Freauff, Bromomisonidazole: Synthesis and characterization of a new radiosensitizer. Radiat. Res. 91, 542–554 (1982).

    CAS  Google Scholar 

  26. D. C. Jette, L. I. Wiebe, And J. D. Chapman, Synthesis and in vivo studies of the radiosensitizer 4-(82Br)bromomisonidazole. Int. J. Nuc. Med. and Biol. 10, 205–210 (1983).

    Article  CAS  Google Scholar 

  27. M. B. Parliament, J. D. Chapman, R. C. Urtasun, A. J. Mcewan, L. Golberg, J. R. Mercer, R. H. Mannan, And L. I. Wiebe, Non-invasive assessment of human tumour hypoxia with Iiodoazomycin arabinoside: preliminary report of a clinical study. Br. J. Cancer 65, 90–95 (1992).

    Article  PubMed  CAS  Google Scholar 

  28. J. S. Rasey, W.-J. Koh, M. L. Evans, L. M. Peterson, T. K. Lewellen, M. M. Graham, And K. A. Krohn, Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients. Int. J. Radiat. Oncol. Biol. Phys. 36, 417–428 (1996).

    Article  PubMed  CAS  Google Scholar 

  29. J. E. Moulder, And S. C. Rockwell, Hypoxic fractions of solid tumors: experimental techniques, methods of analysis and a survey of existing data. Int. J. Radiat. Oncol. Biol. Phys. 10, 695–712 (1984).

    Article  PubMed  CAS  Google Scholar 

  30. J. D. Chapman, A. J. Franko, And C. J. Koch, The fraction of hypoxic clonogenic cells in tumor populations. In: Biological Bases and Clinical Implications of Tumor Radioresistance 61–73, Masson Publishing, NY (1983).

    Google Scholar 

  31. S. M. Evans, W. T. Jenkins, B. Joiner, E. M. Lord, And C. J. Koch, 2-nitroimidazole (EF5) binding predicts radiation sensitivity in individual 9L subcutaneous tumors. Cancer Res. 56, 405–411 (1996).

    PubMed  CAS  Google Scholar 

  32. P. L. Olive, R. E. Durand, J. A. Raleigh, C. Luo, And C. Aquino-Parsons, Comparison between the comet assay and pimonidazole binding for measuring tumour hypoxia. Brit. J. Cancer 83, 1525–1531 (2000).

    Article  CAS  Google Scholar 

  33. M. R. Woods, E. M. Lord, And C. J. Koch, Detection of individual hypoxic cells in multicellular spheroids by flow cytometery using the 2-nitroimidazole EF5, and monoclonal antibodies. Int. J. Radiat. Oncol. Biol. Phys. 34, 93–101 (1996).

    Article  PubMed  CAS  Google Scholar 

  34. P. Vaupel, K. Schlenger, C. Knoop, And M. Hockel, Oxygenatiuon of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized 02 tension measurements. Cancer Res. 51, 3316–3322 (1991).

    PubMed  CAS  Google Scholar 

  35. J. D. Chapman, E. L. Engelhardt, C. C. Stobbe, R. F. Schneider, And G. E. Hanks, Measuring hypoxia and predicting tumor radioresistance with nuclear medicine assays. Radioth. & Oncol. 46, 229–237 (1998).

    Article  CAS  Google Scholar 

  36. L. L. Wiebe, & D. Stypinski, Pharmacokinetics of SPECT radiopharmaceuticals for imaging hypoxic tissues. Quart. J. Nuc. Med. 40, 270–284 (1996).

    CAS  Google Scholar 

  37. A. Nunn, K. Linder, And H. W. Strauss, Nitroimidazoles and imaging hypoxia. Eur. J. Nuc. Med. 22, 265–280 (1995).

    Article  CAS  Google Scholar 

  38. T. J. Tewson, Synthesis of [18F]fluoroetanidazole: a potential new tracer for imaging hypoxia. Nuc. Med. & Biol. 24, 755–760 (1997).

    CAS  Google Scholar 

  39. J. S. Rasey, P. D. Hofstrand, L. K. Chin, And T. K. Tewson, Characterization of [18F]Fluoroetanidazole, a new radiopharmaceutical for detecting tumor hypoxia. J. Nue. Med. 40, 1072–1079 (1999).

    CAS  Google Scholar 

  40. M. M. Graham, L. M. Peterson, J. M. Link, M. L. Evans, J. S. Rasey, W.-J. Koh, J. H. Caldwell, And K. A. Krohn, Fluorine-18-fluoromisonidazole radiation dosimetry in imaging studies. J. Nuc. Med. 38, 1631–1636 (1997).

    CAS  Google Scholar 

  41. B. G. Siim, W. T. Laux, M. D. Rutland, B. N. Palmer, And W. R. Wilson, Scintigraphic imaging of the hypoxia marker (99m)technetium-labeled 2,2’-(1,4-diaminobutane)bis(2methyl-3-butanone) dioxime (99mTc-labeled HL-91; prognox): noninvasive detection of tumor response to the antivascular agent 5,6-dimethylxanthenone-4-acetic acid. Cancer Res. 60, 4582–4588 (2000).

    PubMed  CAS  Google Scholar 

  42. C. J. Koch, S. M. Hahn, K. J. Rockwell, J. M. Covey, W. K. Mckenna, And S. M. Evans, Pharmacokinetics of the 2-Nitroimidazole EF5 [2-(2-nitro-1-H-imidazol-1-yl)-N(2,2,3,3,3-pentafluoropropyl)acetamide] in Human Patients: Implications for Hypoxia Measurements In Vivo. Cancer Chemoth. Pharmacol. 48, 177–187 (2001).

    CAS  Google Scholar 

  43. W. R. Dolbier, A.-R. Li, C. J. Koch, C.-Y. Shiue, And A. V. Kachur, [18F-EF5, a marker for PET detection of hypoxia: Synthesis of precursor and a new fluorination procedure. App1. Rad. and Isot. 54, 73–80 (2001).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. University of Pennsylvania, Radiation Oncolog, Philadelphia, PA, 19104-6072

    Cameron J. Koch & Sydney M. Evans

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  1. Cameron J. Koch
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  1. University of Pennsylvania, Philadelphia, Pennsylvania, USA

    David F. Wilson , Sydney M. Evans , John Biaglow  & Anna Pastuszko , ,  & 

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Koch, C.J., Evans, S.M. (2003). Non-Invasive PET and Spect Imaging of Tissue Hypoxia Using Isotopically Labeled 2-Nitroimidazoles. In: Wilson, D.F., Evans, S.M., Biaglow, J., Pastuszko, A. (eds) Oxygen Transport To Tissue XXIII. Advances in Experimental Medicine and Biology, vol 510. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0205-0_47

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  • DOI: https://doi.org/10.1007/978-1-4615-0205-0_47

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