Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1981 Apr;43(4):443–450. doi: 10.1038/bjc.1981.65

In vitro metabolism of misonidazole.

P D Josephy, B Palcic, L D Skarsgard
PMCID: PMC2010618  PMID: 7236487

Abstract

Misonidazole (MISO) is a nitroimidazole drug currently undergoing clinical trials as a radiosensitizer of hypoxic tumour cells. The drug is also toxic to such cells, probably because of metabolic activation of the nitro group under hypoxia. The metabolic fate of 14C-labelled MISO is examined, using hypoxic mammalian (CHO) cells in vitro. Organic-soluble and acid-soluble metabolites are formed, and radioactivity is bound to macromolecules. The organic-soluble products are separated by TLC and HPLC. Evidence is presented to show that one of the metabolites is hydroxylamino-misonidazole. The significance of metabolic nitroreduction is discussed.

Full text

PDF
443

Images in this article

446Fig. 2
on p.446

Selected References

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

  1. Flockhart I. R., Large P., Troup D., Malcolm S. L., Marten T. R. Pharmacokinetic and metabolic studies of the hypoxic cell radiosensitizer misonidazole. Xenobiotica. 1978 Feb;8(2):97–105. doi: 10.3109/00498257809060388. [DOI] [PubMed] [Google Scholar]
  2. Hall E. J., Roizin-Towle L. Hypoxic sensitizers: radiobiological studies at the cellular level. Radiology. 1975 Nov;117(2):453–457. doi: 10.1148/117.2.453. [DOI] [PubMed] [Google Scholar]
  3. Josephy P. D., Palcic B., Skarsgard L. D. Ascorbate-enhanced cytotoxicity of misonidazole. Nature. 1978 Jan 26;271(5643):370–372. doi: 10.1038/271370a0. [DOI] [PubMed] [Google Scholar]
  4. Mason R. P., Holtzman J. L. The mechanism of microsomal and mitochondrial nitroreductase. Electron spin resonance evidence for nitroaromatic free radical intermediates. Biochemistry. 1975 Apr 22;14(8):1626–1632. doi: 10.1021/bi00679a013. [DOI] [PubMed] [Google Scholar]
  5. Moore B. A., Palcic B., Skarsgard L. D. Radiosensitizing and toxic effects on the 2-nitroimidazole Ro-07-0582 in hypoxic mammation cells. Radiat Res. 1976 Sep;67(3):459–473. [PubMed] [Google Scholar]
  6. Sealy R. C., Swartz H. M., Olive P. L. Electron spin resonance-spin trapping. Detection of superoxide formation during aerobic microsomal reduction of nitro-compounds. Biochem Biophys Res Commun. 1978 May 30;82(2):680–684. doi: 10.1016/0006-291x(78)90928-2. [DOI] [PubMed] [Google Scholar]
  7. Taylor Y. C., Rauth A. M. Differences in the toxicity and metabolism of the 2-nitroimidazole misonidazole (Ro-07-0582) in HeLa and Chinese hamster ovary cells. Cancer Res. 1978 Sep;38(9):2745–2752. [PubMed] [Google Scholar]
  8. Taylor Y. C., Rauth A. M. Sulphydryls, ascorbate and oxygen as modifiers of the toxicity and metabolism of misonidazole in vitro. Br J Cancer. 1980 Jun;41(6):892–900. doi: 10.1038/bjc.1980.166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Varghese A. J., Gulyas S., Mohindra J. K. Hypoxia-dependent reduction of 1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol by Chinese hamster ovary cells and KHT tumor cells in vitro and in vivo. Cancer Res. 1976 Oct;36(10):3761–3765. [PubMed] [Google Scholar]
  10. Varghese A. J., Whitmore G. F. Binding of nitroreduction products of misonidazole to nucleic acids and protein. Cancer Clin Trials. 1980 Spring;3(1):43–46. [PubMed] [Google Scholar]
  11. Varghese A. J., Whitmore G. F. Binding to cellular macromolecules as a possible mechanism for the cytotoxicity of misonidazole. Cancer Res. 1980 Jul;40(7):2165–2169. [PubMed] [Google Scholar]
  12. Wardman P. The use of nitroaromatic compounds as hypoxic cell radiosensitizers. Curr Top Radiat Res Q. 1977 Aug;11(4):347–398. [PubMed] [Google Scholar]
  13. Wasserman T. H., Phillips T. L., Van Raalte G., Urtasun R., Partington J., Koziol D., Schwade J. G., Gangji D., Strong J. M. The neurotoxicity of misonidazole: potential modifying role of phenytoin sodium and dexamethasone. Br J Radiol. 1980 Feb;53(626):172–173. doi: 10.1259/0007-1285-53-626-172. [DOI] [PubMed] [Google Scholar]
  14. Whitmore G. F., Gulyas S., Varghese A. J. Sensitizing and toxicity properties of misonidazole and its derivatives. Br J Cancer Suppl. 1978 Jun;3:115–119. [PMC free article] [PubMed] [Google Scholar]
  15. Wong T. W., Whitmore G. F., Gulyas S. Studies on the toxicity and radiosensitizing ability of misonidazole under conditions of prolonged incubation. Radiat Res. 1978 Sep;75(3):541–555. [PubMed] [Google Scholar]
  16. Workman P. Pharmacokinetics of hypoxic cell radiosensitizers: a review. Cancer Clin Trials. 1980 Fall;3(3):237–251. [PubMed] [Google Scholar]

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

RESOURCES