Pharmaceutical Research

, Volume 16, Issue 5, pp 743–750 | Cite as

Noninvasive Assessment of Tumor Hypoxia with 99mTc Labeled Metronidazole

  • David J. Yang
  • Seyfettin Ilgan
  • Tetsuya Higuchi
  • Fereshteh Zareneyrizi
  • Chang-Sok Oh
  • Chun-Wei Liu
  • E. Edmund Kim
  • Donald A. Podoloff
Article

Abstract

Purpose. The assessment of tumor hypoxia by imaging modality prior to radiation therapy would provide a rational means of selecting patients for treatment with radiosensitizers or bioreductive drugs. This study aimed to develop a 99mTc-labeled metronidazole (MN) using ethylene-dicysteine (EC) as a chelator and evaluate its potential use to image tumor hypoxia.

Methods. EC was conjugated to amino analogue of MN using Sulfo-N-hydroxysuccinimide and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide-HCl as coupling agents, the yield was 55%. Tissue distribution of 99mTc-EC-MN was determined in breast tumor-bearing rats at 0.5, 2, and 4 hrs. Planar imaging and whole-body autoradiograms were performed. The data was compared to that using 99mTc-EC (control), [l8F]fluoromisonidazole (FMISO) and [131I] iodomisonidazole (IMISO).

Results. In vivo biodistribution of 99mTc-EC-MN in breast tumor-bearing rats showed increased tumor-to-blood and tumor-to-muscle ratios as a function of time. Conversely, tumor-to-blood values showed time-dependent decrease with 99mTc-EC in the same time period. Planar images and autoradiograms confirmed that the tumors could be visualized clearly with 99mTc-EC-MN from 0.5 to 4 hrs. There was no significant difference of tumor-to-blood count ratios between 99mTc-EC-MN and [131I]IMISO at 2 and 4 hrs postinjection. From 0.5 to 4 hrs, both 99mTc-EC-MN and [131I]IMISO have higher tumor-to-muscle ratios compared to [18]FMISO.

Conclusions. It is feasible to use 99mTc-EC-MN to image tumor hypoxia.

metronidazole 99mTc tumor hypoxia imaging radiosensitizer 

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REFERENCES

  1. 1.
    E. J. Hall. The oxygen effect and reoxygenation. In E. J. Hall (ed.) Radiobiology for the radiobiologist, 3rd edition. J. B. Lippincott Co., Philadelphia, PA, 1988, pp. 137-160.Google Scholar
  2. 2.
    R. S. Bush, R. D. T. Jenkins, W. E. C. Allt, F. A. Beale, H. Bena, A. J. Dembo, and J. F. Pringle. Definitive evidence for hypoxic cells influencing cure in cancer therapy. Br. J. Cancer 37(Suppl. III):302-306 (1978).Google Scholar
  3. 3.
    L. H. Gray, A. D. Conger, M. Elbert, S. Morsney, and O.C.A. Scold. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br. J. Radiol. 26:638-648 (1953).PubMedGoogle Scholar
  4. 4.
    S. Dische. A review of hypoxic-cell radiosensitization. Int. J. Radiat. Oncol. Biol. Phys. 20:147-152 (1991).PubMedGoogle Scholar
  5. 5.
    R. A. Gatenby, H. B. Kessler, J. S. Rosenblum, L. R. Coia, P. J. Moldofsky, W. H. Hartz, and G. J. Broder. Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 14:831-838 (1988).PubMedGoogle Scholar
  6. 6.
    M. Nordsmark, M. Overgaard, and J. Overgaard. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother. Oncol. 41:31-39 (1996).PubMedGoogle Scholar
  7. 7.
    W-J Koh, J. S. Rasey, M. L. Evans, J. R. Grierson, T. K. Lewellen, M. M. Graham, K. A. Krohn, and T. W. Griffin. Imaging of hypoxia in human tumors with 18F fluoromisonidazole. Int. J. Radiat. Oncol. Biol. Phys. 22:199-212 (1992).PubMedGoogle Scholar
  8. 8.
    P. E. T. Valk, C. A. Mathis, M. D. Prados, J. C. Gilbert, and T. F. Budinger. Hypoxia in human gliomas: Demonstration by PET with [18F]fluoromisonidazole. J. Nucl. Med. 33:2133-2137 (1992).PubMedGoogle Scholar
  9. 9.
    G. V. Martin, J. H. Caldwell, J. S. Rasey, Z. Grunbaum, M. Cerqueia, and K. A. Krohn. Enhanced binding of the hypoxic cell marker [18F]fluoromisonidazole in ischemic myocardium. J. Nucl. Med. 30:194-201 (1989).PubMedGoogle Scholar
  10. 10.
    J. S. Rasey, W. J. Koh, J. R. Grieson, Z. Grunbaum, and K. A. Krohn. Radiolabeled fluoromisonidazole as an imaging agent for tumor hypoxia. Int J. Radiat. Oncol. Biol. Phys. 17:985-991 (1989).PubMedGoogle Scholar
  11. 11.
    J. S. Rasey, N. J. Nelson, L. Chin, M. L. Evans, and Z. Grunbaum. Characterization of the binding of labeled fluoromisonidazole in cells in vitro. Radiat. Res. 122:301-308 (1990).PubMedGoogle Scholar
  12. 12.
    D. J. Yang, S. Wallace, A. Cherif, C. Li, M. B. Gretzer, E. E. Kim, and D. A. Podoloff. Development of F-18-labeled fluoroerythronitroimidazole as a PET agent for imaging tumor hypoxia. Radiology 194:795-800 (1995).PubMedGoogle Scholar
  13. 13.
    A. Cherif, S. Wallace, D. J. Yang, R. Newman, V. Wilson, A. Nornoo, T. Inoue, C. Kim, L-R Kuang, E. E. Kim, and D. A. Podoloff. Development of new markers for hypoxic cells: [131I]io-domisonidazole and [131I]iodoerythronitroimidazole. J. Drug Targeting 4:31-39 (1996).Google Scholar
  14. 14.
    B. A. Teicher and E. A. Sotomayor. Chemical radiation sensitizers and protectors. In W. O. Foye (ed.), Cancer Chemotherapeutic Agents, American Chemical Society, Washington, D. C., 1995, pp. 501-527.Google Scholar
  15. 15.
    G. Johnson, K. N. Nguyen, Z. Lui, P. Gao, B. Edwards, C. M. Archer, A. C. King, T. L. North, R. D. Okada, and W. K. Warren. HL91 Technetium-99m: Kinetics of a new hypoxia avid imaging agent in normal and ischemic myocardium as assessed by gamma camera images. J. Am. Coll. Cardiol. 407A (1996).Google Scholar
  16. 16.
    K. Fukuchi, H. Kusuoka, K. Yutani, S. Hasegawa, and T. Nishimura. Assessment of reperfused myocardium using new hypoxia avid imaging agent Tc-99m HL91. J. Nucl. Med. 37:94 (Abstract) (1996).Google Scholar
  17. 17.
    T. Melo, J. Duncan, J. R. Ballinger, and A. M. Rauth. BMS 194796, a second generation Tc-99m labelled 2-nitroimidazole for imaging hypoxia in tumors. J. Nucl. Med. 39:219 (Abstract) (1998).Google Scholar
  18. 18.
    X. Zhang, T. Melo, J. R. Ballinger, and A. M. Rauth. Evaluation of Tc-99m butyleneamino oxime (BnAO), a non-nitroaromatic agent for imaging hypoxia in tumors. J. Nucl. Med. 39:216 (Abstract) (1998).PubMedGoogle Scholar
  19. 19.
    A. Davison, A. G. Jones, C. Orvig, and M. Sohn. A new class of oxotechnetium(+5) chelate complexes containing a TcON2S2 Core. Inorg. Chem. 20:1629-1632 (1981).Google Scholar
  20. 20.
    A. M. Verbruggen, D. L. Nosco, C. G. Van Nerom, G. M. Bormans, P. J. Adriaens, and M. J. De Roo. Tc-99m-L,L-ethylenedicysteine: A renal imaging agent. I. Labelling and evaluation in animals. J. Nucl. Med. 33:551-557 (1992).PubMedGoogle Scholar
  21. 21.
    C. G. Van Nerom, G. M. Bormans, M. J. De Roo, and A. M. Verbruggen. First experience in healthy volunteers with Tc-99m-L,L-ethylenedicysteine, a new renal imaging agent. Eur. J. Nucl. Med. 20:738-746 (1993).PubMedGoogle Scholar
  22. 22.
    M. J. Surma, J. Wiewiora, and J. Liniecki. Usefulness of Tc-99m-N,N′-ethylene-1-dicysteine complex for dynamic kidney investigations. Nucl. Med. Comm. 15:628-635 (1994).Google Scholar
  23. 23.
    S. Ratner and H. T. Clarke. The action of formaldehyde upon cysteine. J. Am. Chem. Soc. 59:200-206 (1937).Google Scholar
  24. 24.
    P. Blondeau, C. Berse, and D. Gravel. Dimerization of an intermediate during the sodium in liquid ammonia reduction of L-thiazolidine-4-carboxylic acid. Can. J. Chem. 45:49-52 (1967).Google Scholar
  25. 25.
    M. P. Hay, W. R. Wilson, J. W. Moselen, B. D. Palmer, and W. A. Denny. Hypoxia-selective antitumor agents. Bis(nitroimidazolyl)alkanecarboxamides: a new class of hypoxia-selective cytotoxins and hypoxic cell radiosensitizers. J. Med. Chem. 37:381-391 (1994).PubMedGoogle Scholar
  26. 26.
    A. Cherif, D. J. Yang, W. Tansey, E. E. Kim, and S. Wallace. Synthesis of [18F]fluoromisonidazole. Pharm. Res. 11:466-469 (1994).PubMedGoogle Scholar
  27. 27.
    G. V. Martin, J. H. Cardwell, M. M. Graham, J. R. Grierson, K. Kroll, M. J. Xowna, T. K. Lewellen, J. S. Rasey, J. J. Casciari, and K. A. Krohn. Noninvasive detection of hypoxic myocardium using [18F]fluoromisonidazole and PET. J. Nucl. Med. 33:2202-2208 (1992).PubMedGoogle Scholar
  28. 28.
    S. H. Yeh, R. S. Liu, H. H. Hu, C. P. Chang, L. S. Chu, K. L. Chou, and L. C. Wu. Ischemic penumbra in acute stroke: demonstration by PET with fluorine-18 fluoromisonidazole. J. Nucl. Med. 35:(5)205 (Abstract) (1994).Google Scholar
  29. 29.
    S. H. Yeh, R. S. Liu, L. C. Wu, D. J. Yang, S. H. Yen, C. W. Chang, T. W. Yu, K. L. Chou, and K. Y. Chen. Fluorine-18 fluoromisonidazole tumor to muscle retention ratio for the detection of hypoxia in nasopharyngeal carcinoma. Eur. J. Nucl. Med. 23:1378-1383 (1996).PubMedGoogle Scholar
  30. 30.
    R. S. Liu, S. H. Yeh, C. P. Chang, L. S. Chu, M. T. Lui, K. L. Chou, and L. C. Wu. Detection of odontogenic infections by [18F]fluoromisonidazole. J. Nucl. Med. 35:113 (Abstract) (1994).PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1999

Authors and Affiliations

  • David J. Yang
    • 1
  • Seyfettin Ilgan
    • 1
  • Tetsuya Higuchi
    • 1
  • Fereshteh Zareneyrizi
    • 1
  • Chang-Sok Oh
    • 1
  • Chun-Wei Liu
    • 1
  • E. Edmund Kim
    • 1
  • Donald A. Podoloff
    • 1
  1. 1.Department of Nuclear MedicineThe University of Texas M. D. Anderson Cancer CenterHouston

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