Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1992 Dec;66(6):1103–1108. doi: 10.1038/bjc.1992.418

Nitroimidazole adducts as markers for tissue hypoxia: mechanistic studies in aerobic normal tissues and tumour cells.

M B Parliament 1, L I Wiebe 1, A J Franko 1
PMCID: PMC1978026  PMID: 1280990

Abstract

Two aspects of the aerobic metabolism of nitroimidazole markers for hypoxia were investigated. Several normal murine tissues which are likely to be well oxygenated bind misonidazole at rates comparable to those of hypoxic regions in tumours. The possibility that this aerobic activation occurs via an oxygen independent process such as an initial two electron reduction was studied. Binding to the oesophageal mucosa of mice which occurred under hypoxia in vitro was inhibited by at least 95% in the presence of 10% oxygen. Dicoumarol, an inhibitor of DT-diaphorase, was shown to cause only small reductions in misonidazole binding to oesophageal epithelium and smooth muscle in vitro and to EMT6 tumours, liver, oesophageal and tracheal epithelium, parotid gland and smooth muscle in vivo. Thus an oxygen-insensitive process is not a major cause of the high binding rate in oesophageal mucosa, and may not contribute significantly to the observed binding in other normal tissues. It has been suggested that metabolism of nitroimidazoles by aerobic cells in tumours might be sufficient to minimise access of these compounds to hypoxic regions, particularly at the micromolar concentrations currently in use clinically. The uptake of 125I-iodoazomycin arabinoside by RIF-1 and EMT6 tumours was found to be directly proportional to injected dose over concentrations between 0.5 and 50 microM. Labelling of hypoxic regions in EMT6 tumours by high specific activity 3H-misonidazole at 1 microM was found to be similar to that obtained at 50 microM.

Full text

PDF
1103

Images in this article

1105Figure 1
on p.1105

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akel G., Benard P., Canal P., Soula G. Distribution and tumor penetration properties of a radiosensitizer 2-[14C] misonidazole (Ro 07-0582), in mice and rats as studied by whole-body autoradiography. Cancer Chemother Pharmacol. 1986;17(2):121–126. doi: 10.1007/BF00306739. [DOI] [PubMed] [Google Scholar]
  2. Brown J. M., Lemmon M. J. SR 4233: a tumor specific radiosensitizer active in fractionated radiation regimes. Radiother Oncol. 1991;20 (Suppl 1):151–156. doi: 10.1016/0167-8140(91)90203-s. [DOI] [PubMed] [Google Scholar]
  3. Chaplin D. J., Horsman M. R., Trotter M. J. Effect of nicotinamide on the microregional heterogeneity of oxygen delivery within a murine tumor. J Natl Cancer Inst. 1990 Apr 18;82(8):672–676. doi: 10.1093/jnci/82.8.672. [DOI] [PubMed] [Google Scholar]
  4. Chapman J. D., Baer K., Lee J. Characteristics of the metabolism-induced binding of misonidazole to hypoxic mammalian cells. Cancer Res. 1983 Apr;43(4):1523–1528. [PubMed] [Google Scholar]
  5. Chapman J. D., Franko A. J., Sharplin J. A marker for hypoxic cells in tumours with potential clinical applicability. Br J Cancer. 1981 Apr;43(4):546–550. doi: 10.1038/bjc.1981.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chapman J. D. Hypoxic sensitizers--implications for radiation therapy. N Engl J Med. 1979 Dec 27;301(26):1429–1432. doi: 10.1056/NEJM197912273012606. [DOI] [PubMed] [Google Scholar]
  7. Cobb L. M., Hacker T., Nolan J. NAD(P)H nitroblue tetrazolium reductase levels in apparently normoxic tissues: a histochemical study correlating enzyme activity with binding of radiolabelled misonidazole. Br J Cancer. 1990 Apr;61(4):524–529. doi: 10.1038/bjc.1990.118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cobb L. M., Nolan J., Butler S. A. Distribution of pimonidazole and RSU 1069 in tumour and normal tissues. Br J Cancer. 1990 Dec;62(6):915–918. doi: 10.1038/bjc.1990.408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cobb L. M., Nolan J., Butler S. Tissue distribution of 14C- and 3H-labelled misonidazole in the tumor-bearing mouse. Int J Radiat Oncol Biol Phys. 1990 Feb;18(2):347–351. doi: 10.1016/0360-3016(90)90099-6. [DOI] [PubMed] [Google Scholar]
  10. Cobb L. M., Nolan J., O'Neill P. Microscopic distribution of misonidazole in mouse tissues. Br J Cancer. 1989 Jan;59(1):12–16. doi: 10.1038/bjc.1989.4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Coleman C. N., Urtasun R. C., Wasserman T. H., Hancock S., Harris J. W., Halsey J., Hirst V. K. Initial report of the phase I trial of the hypoxic cell radiosensitizer SR-2508. Int J Radiat Oncol Biol Phys. 1984 Sep;10(9):1749–1753. doi: 10.1016/0360-3016(84)90542-x. [DOI] [PubMed] [Google Scholar]
  12. Franko A. J., Chapman J. D. Binding of 14C-misonidazole to hypoxic cells in V79 spheroids. Br J Cancer. 1982 May;45(5):694–699. doi: 10.1038/bjc.1982.110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Franko A. J., Koch C. J., Garrecht B. M., Sharplin J., Hughes D. Oxygen dependence of binding of misonidazole to rodent and human tumors in vitro. Cancer Res. 1987 Oct 15;47(20):5367–5376. [PubMed] [Google Scholar]
  14. Franko A. J. Misonidazole and other hypoxia markers: metabolism and applications. Int J Radiat Oncol Biol Phys. 1986 Jul;12(7):1195–1202. doi: 10.1016/0360-3016(86)90257-9. [DOI] [PubMed] [Google Scholar]
  15. Garrecht B. M., Chapman J. D. The labelling of EMT-6 tumours in BALB/C mice with 14C-misonidazole. Br J Radiol. 1983 Oct;56(670):745–753. doi: 10.1259/0007-1285-56-670-745. [DOI] [PubMed] [Google Scholar]
  16. Guichard M. The use of fluorocarbon emulsions in cancer radiotherapy. Radiother Oncol. 1991;20 (Suppl 1):59–64. doi: 10.1016/0167-8140(91)90189-n. [DOI] [PubMed] [Google Scholar]
  17. Horsman M. R., Wood P. J., Chaplin D. J., Brown J. M., Overgaard J. The potentiation of radiation damage by nicotinamide in the SCCVII tumour in vivo. Radiother Oncol. 1990 May;18(1):49–57. doi: 10.1016/0167-8140(90)90022-o. [DOI] [PubMed] [Google Scholar]
  18. Keyes S. R., Rockwell S., Sartorelli A. C. Enhancement of mitomycin C cytotoxicity to hypoxic tumor cells by dicoumarol in vivo and in vitro. Cancer Res. 1985 Jan;45(1):213–216. [PubMed] [Google Scholar]
  19. Koch C. J., Stobbe C. C., Baer K. A. Metabolism induced binding of 14C-misonidazole to hypoxic cells: kinetic dependence on oxygen concentration and misonidazole concentration. Int J Radiat Oncol Biol Phys. 1984 Aug;10(8):1327–1331. doi: 10.1016/0360-3016(84)90342-0. [DOI] [PubMed] [Google Scholar]
  20. MacManus M. P., Maxwell A. P., Abram W. P., Bridges J. M. The effect of hypobaric hypoxia on misonidazole binding in normal and tumour-bearing mice. Br J Cancer. 1989 Mar;59(3):349–352. doi: 10.1038/bjc.1989.69. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mannan R. H., Somayaji V. V., Lee J., Mercer J. R., Chapman J. D., Wiebe L. I. Radioiodinated 1-(5-iodo-5-deoxy-beta-D-arabinofuranosyl)-2-nitroimidazole (iodoazomycin arabinoside: IAZA): a novel marker of tissue hypoxia. J Nucl Med. 1991 Sep;32(9):1764–1770. [PubMed] [Google Scholar]
  22. Marshall R. S., Paterson M. C., Rauth A. M. Deficient activation by a human cell strain leads to mitomycin resistance under aerobic but not hypoxic conditions. Br J Cancer. 1989 Mar;59(3):341–346. doi: 10.1038/bjc.1989.67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Maxwell A. P., MacManus M. P., Gardiner T. A. Misonidazole binding in murine liver tissue: a marker for cellular hypoxia in vivo. Gastroenterology. 1989 Nov;97(5):1300–1303. doi: 10.1016/0016-5085(89)91703-4. [DOI] [PubMed] [Google Scholar]
  24. Olive P. L., Rasey J. S., Durand R. E. Comparison between the binding of [3H]misonidazole and AF-2 in Chinese hamster V79 spheroids. Radiat Res. 1986 Jan;105(1):105–114. [PubMed] [Google Scholar]
  25. Overgaard J., Sand Hansen H., Lindeløv B., Overgaard M., Jørgensen K., Rasmusson B., Berthelsen A. Nimorazole as a hypoxic radiosensitizer in the treatment of supraglottic larynx and pharynx carcinoma. First report from the Danish Head and Neck Cancer Study (DAHANCA) protocol 5-85. Radiother Oncol. 1991;20 (Suppl 1):143–149. doi: 10.1016/0167-8140(91)90202-r. [DOI] [PubMed] [Google Scholar]
  26. Parliament M. B., Chapman J. D., Urtasun R. C., McEwan A. J., Golberg L., Mercer J. R., Mannan R. H., Wiebe L. I. Non-invasive assessment of human tumour hypoxia with 123I-iodoazomycin arabinoside: preliminary report of a clinical study. Br J Cancer. 1992 Jan;65(1):90–95. doi: 10.1038/bjc.1992.17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Rasey J. S., Koh W. J., Grierson J. R., Grunbaum Z., Krohn K. A. Radiolabelled fluoromisonidazole as an imaging agent for tumor hypoxia. Int J Radiat Oncol Biol Phys. 1989 Nov;17(5):985–991. doi: 10.1016/0360-3016(89)90146-6. [DOI] [PubMed] [Google Scholar]
  29. Rauth A. M. Pharmacology and toxicology of sensitizers: mechanism studies. Int J Radiat Oncol Biol Phys. 1984 Aug;10(8):1293–1300. doi: 10.1016/0360-3016(84)90335-3. [DOI] [PubMed] [Google Scholar]
  30. Teicher B. A., Rose C. M. Oxygen-carrying perfluorochemical emulsion as an adjuvant to radiation therapy in mice. Cancer Res. 1984 Oct;44(10):4285–4288. [PubMed] [Google Scholar]
  31. Twentyman P. R., Brown J. M., Gray J. W., Franko A. J., Scoles M. A., Kallman R. F. A new mouse tumor model system (RIF-1) for comparison of end-point studies. J Natl Cancer Inst. 1980 Mar;64(3):595–604. [PubMed] [Google Scholar]
  32. Urtasun R. C., Koch C. J., Franko A. J., Raleigh J. A., Chapman J. D. A novel technique for measuring human tissue pO2 at the cellular level. Br J Cancer. 1986 Sep;54(3):453–457. doi: 10.1038/bjc.1986.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Van Os-Corby D. J., Chapman J. D. In vitro binding of 14C-misonidazole to hepatocytes and hepatoma cells. Int J Radiat Oncol Biol Phys. 1986 Jul;12(7):1251–1254. doi: 10.1016/0360-3016(86)90270-1. [DOI] [PubMed] [Google Scholar]
  34. Van Os-Corby D. J., Koch C. J., Chapman J. D. Is misonidazole binding to mouse tissues a measure of cellular pO2? Biochem Pharmacol. 1987 Oct 15;36(20):3487–3494. doi: 10.1016/0006-2952(87)90330-3. [DOI] [PubMed] [Google Scholar]
  35. Wasserman T. H., Lee D. J., Cosmatos D., Coleman N., Phillips T., Davis L., Marcial V., Stetz J. Clinical trials with etanidazole (SR-2508) by the Radiation Therapy Oncology Group (RTOG). Radiother Oncol. 1991;20 (Suppl 1):129–135. doi: 10.1016/0167-8140(91)90200-z. [DOI] [PubMed] [Google Scholar]
  36. Workman P., Walton M. I., Powis G., Schlager J. J. DT-diaphorase: questionable role in mitomycin C resistance, but a target for novel bioreductive drugs? Br J Cancer. 1989 Nov;60(5):800–803. doi: 10.1038/bjc.1989.364. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES