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. 1981 Mar;43(3):355–366. doi: 10.1038/bjc.1981.56

Low concentrations of misonidazole counteract effects of extreme hypoxia on cells in S.

E O Pettersen, T Lindmo
PMCID: PMC2010604  PMID: 7013776

Abstract

Populations of NHIK 3025 cells synchronized by mitotic selection were exposed at 37 degrees C to extreme hypoxia in absence and presence of misonidazole (MISO). Cells in G1, S or G2 and mitosis were treated for 3 h. Inhibition of cell-cycle progression by this treatment was measured by flow cytometry of DNA histograms and cell inactivation was measured by colony formation. The exposure to hypoxia alone of cells in G1 or in G2 and mitosis led to only minor cell-cycle inhibition, and hardly reduced cell survival. However, the exposure of cells in S to hypoxia alone had a strong inhibitory effect on cell-cycle progression, and cell survival was only 40% of untreated cells. Low concentrations of MISO (0.05-0.4 mM) during exposure of cells in S to hypoxia, produced less cell-cycle inhibition than after hypoxia alone, and cell survival was restored to 100%. The presence of MISO during the 3h exposure to hypoxia of cells in G1 or in G2 and mitosis only increased the effects of hypoxia alone. MISO at concentrations greater than 0.8 mM during hypoxia produced cell inactivation, for all phases of the cell cycle, comparable to that already known from the literature.

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Selected References

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  1. Adams G. E., Cooke M. S. Electron-affinic sensitization. I. A structural basis for chemical radiosensitizers in bacteria. Int J Radiat Biol Relat Stud Phys Chem Med. 1969 Jul;15(5):457–471. doi: 10.1080/09553006914550741. [DOI] [PubMed] [Google Scholar]
  2. Ash D. V., Smith M. R., Bugden R. D. Distribution of misonidazole in human tumours and normal tissues. Br J Cancer. 1979 May;39(5):503–509. doi: 10.1038/bjc.1979.93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Astor M., Hall E. J. Misonidazole and MTDQ in combination: cytotoxic and radiosensitizing properties in hypoxic mammalian cells. Br J Cancer. 1979 May;39(5):510–515. doi: 10.1038/bjc.1979.94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bakke O., Pettersen E. O. A fast and accurate method for calculating Engelberg's synchronization index. Cell Tissue Kinet. 1976 Jul;9(4):389–393. doi: 10.1111/j.1365-2184.1976.tb01287.x. [DOI] [PubMed] [Google Scholar]
  5. Bedford J. S., Mitchell J. B. The effect of hypoxia on the growth and radiation response of mammalian cells in culture. Br J Radiol. 1974 Oct;47(562):687–696. doi: 10.1259/0007-1285-47-562-687. [DOI] [PubMed] [Google Scholar]
  6. Biaglow J. E., Greenstock C. L., Durand R. E. Effects of sensitizers on cell respiration: 1. Factors influencing the effects of hypoxic cell radiosensitizers on oxygen utilization of tumour and cultured mammalian cells. Br J Cancer Suppl. 1978 Jun;3:145–149. [PMC free article] [PubMed] [Google Scholar]
  7. Biaglow J. E. The effect of hypoxic cell radiosensitizing drugs on cellular oxygen utilization. Pharmacol Ther. 1980;10(2):283–299. doi: 10.1016/0163-7258(80)90084-4. [DOI] [PubMed] [Google Scholar]
  8. Born R., Hug O., Trott K. R. The effect of prolonged hypoxia on growth and viability of Chinese hamster cells. Int J Radiat Oncol Biol Phys. 1976 Jul-Aug;1(7-8):687–697. doi: 10.1016/0360-3016(76)90151-6. [DOI] [PubMed] [Google Scholar]
  9. Brown J. M., Yu N. Y., Workman P. Pharmacokinetic considerations in testing hypoxic cell radiosensitizers in mouse tumours. Br J Cancer. 1979 Mar;39(3):310–320. doi: 10.1038/bjc.1979.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Crissman H. A., Tobey R. A. Cell-cycle analysis in 20 minutes. Science. 1974 Jun 21;184(4143):1297–1298. doi: 10.1126/science.184.4143.1297. [DOI] [PubMed] [Google Scholar]
  11. Dean P. N., Jett J. H. Mathematical analysis of DNA distributions derived from flow microfluorometry. J Cell Biol. 1974 Feb;60(2):523–527. doi: 10.1083/jcb.60.2.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Denekamp J. Cytotoxicity and radiosensitization in mouse and man. Br J Radiol. 1978 Aug;51(608):636–637. doi: 10.1259/0007-1285-51-608-636. [DOI] [PubMed] [Google Scholar]
  13. Dische S., Saunders M. I., Flockhart I. R. The optimum regime for the administration of misonidazole and the establishment of multi-centre clinical trials. Br J Cancer Suppl. 1978 Jun;3:318–321. [PMC free article] [PubMed] [Google Scholar]
  14. Durand R. E., Biaglow J. E., Greenstock C. L. Effects of sensitizers on cell respiration: III. The effects of hypoxic cell radiosensitizers on oxidative metabolism and the radiation response of an in vitro tumour model. Br J Cancer Suppl. 1978 Jun;3:150–153. [PMC free article] [PubMed] [Google Scholar]
  15. Durand R. E., Biaglow J. E. Radiosensitization of hypoxic cells of an in vitro tumor model by respiratory inhibitors. Radiat Res. 1977 Feb;69(2):359–366. [PubMed] [Google Scholar]
  16. Flockhart I. R., Sheldon P. W., Stratford I. J., Watts M. E. A metabolite of the 2-nitroimidazole misonidazole with radiosensitizing properties. Int J Radiat Biol Relat Stud Phys Chem Med. 1978 Jul;34(1):91–94. doi: 10.1080/09553007814550661. [DOI] [PubMed] [Google Scholar]
  17. Geard C. R., Povlas S. F., Astor M. B., Hall E. J. Cytological effects of 1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol (misonidazole) on hypoxic mammalian cells in vitro. Cancer Res. 1978 Mar;38(3):644–649. [PubMed] [Google Scholar]
  18. Gray A. J., Dische S., Adams G. E., Flockhart I. R., Foster J. L. Clinical testing of the radiosensitiser Ro-07-0582. I. Dose tolerance, serum and tumour concentrations. Clin Radiol. 1976 Apr;27(2):151–157. doi: 10.1016/s0009-9260(76)80137-7. [DOI] [PubMed] [Google Scholar]
  19. Gregg C. T., Machinist J. M., Currie W. D. Glycolytic and respiratory properties of intact mammalian cells: inhibitor studies. Arch Biochem Biophys. 1968 Sep 20;127(1):101–111. doi: 10.1016/0003-9861(68)90206-3. [DOI] [PubMed] [Google Scholar]
  20. Hall E. J., Astor M., Geard C., Biaglow J. Cytotoxicity of Ro-07-0582; enhancement by hyperthermia and protection by cysteamine. Br J Cancer. 1977 Jun;35(6):809–815. doi: 10.1038/bjc.1977.122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hall E. J., Astor M., Osmak R., Shapiro P., August L. A comparison of two nitroimidazoles and a dihydroquinoline as radiosensitizers and cytotoxic agents. Int J Radiat Oncol Biol Phys. 1979 Oct;5(10):1781–1786. doi: 10.1016/0360-3016(79)90561-3. [DOI] [PubMed] [Google Scholar]
  22. Hall E. J., Biaglow J. Ro-07-0582 as a radiosensitizer and cytotoxic agent. Int J Radiat Oncol Biol Phys. 1977 May-Jun;2(5-6):521–530. doi: 10.1016/0360-3016(77)90163-8. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Koch C. J., Kruuv J., Frey H. E., Snyder R. A. Plateau phase in growth induced by hypoxia. Int J Radiat Biol Relat Stud Phys Chem Med. 1973 Jan;23(1):67–74. doi: 10.1080/09553007314550061. [DOI] [PubMed] [Google Scholar]
  25. Lindmo T., Aarnaes E. Selection of optimal model for the DNA histogram by analysis of error of estimated parameters. J Histochem Cytochem. 1979 Jan;27(1):297–304. doi: 10.1177/27.1.374590. [DOI] [PubMed] [Google Scholar]
  26. Lindmo T., Pettersen E. O. Delay of cell cycle progression after X-irradiation of synchronized populations of human cells (NHIK 3025) in culture. Cell Tissue Kinet. 1979 Jan;12(1):43–57. doi: 10.1111/j.1365-2184.1979.tb00112.x. [DOI] [PubMed] [Google Scholar]
  27. Lindmo T., Pettersen E. O., Wibe E. Cell-cycle inhibition by misonidazole of human cells cultivated in vitro under aerobic conditions. Br J Cancer. 1979 Nov;40(5):755–760. doi: 10.1038/bjc.1979.257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lindmo T., Steen H. B. Flow cytometric measurement of the polarization of fluorescence from intracellular fluorescein in mammalian cells. Biophys J. 1977 May;18(2):173–187. doi: 10.1016/S0006-3495(77)85606-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Littbrand B., Révész L. Survival of cells in anoxia. Br J Radiol. 1968 Jun;41(486):479–480. doi: 10.1259/0007-1285-41-486-479. [DOI] [PubMed] [Google Scholar]
  30. Lovhaug D., Wibe E., Oftebro R., Pettersen E. O., Brustad T. Recovery from x-ray induced damage in human cells grown in culture. Neoplasma. 1977;24(5):513–520. [PubMed] [Google Scholar]
  31. Lücke-Huhle C., Dertinger H. Kinetic response of an in vitro "tumour-model" (V 79 spheroids) to 42 degrees C hyperthermia. Eur J Cancer. 1977 Jan;13(1):23–28. doi: 10.1016/0014-2964(77)90225-0. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. Mustea I., Bara A., Petrescu I., Révész L. Effect of anoxic radiosensitizers on cellular and mitochondrial oxygen consumption and respiration control ratio. Br J Cancer Suppl. 1978 Jun;3:159–162. [PMC free article] [PubMed] [Google Scholar]
  34. Olive P. L., Durand R. E. Activation of radiosensitizers by hypoxic cells. Br J Cancer Suppl. 1978 Jun;3:124–128. [PMC free article] [PubMed] [Google Scholar]
  35. PUCK T. T., CIECIURA S. J., FISHER H. W. Clonal growth in vitro of human cells with fibroblastic morphology; comparison of growth and genetic characteristics of single epithelioid and fibroblast-like cells from a variety of human organs. J Exp Med. 1957 Jul 1;106(1):145–158. doi: 10.1084/jem.106.1.145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Pettersen E. O., Bakke O., Lindmo T., Oftebro R. Cell cycle characteristics of synchronized and asynchronous populations of human cells and effect of cooling of selected mitotic cells. Cell Tissue Kinet. 1977 Nov;10(6):511–522. doi: 10.1111/j.1365-2184.1977.tb00309.x. [DOI] [PubMed] [Google Scholar]
  37. Pettersen E. O., Oftebro R., Brustad T. X-ray inactivation of human cells in tissue culture under aerobic and extremely hypoxic conditions in the presence and absence of TMPN. Int J Radiat Biol Relat Stud Phys Chem Med. 1973 Sep;24(3):285–296. doi: 10.1080/09553007314551121. [DOI] [PubMed] [Google Scholar]
  38. Pettersen E. O. Radiosensitizing and toxic effects of the 2-nitroimidazole Ro-07-0582 in different phases of the cell cycle of extremely hypoxic human cells in vitro. Radiat Res. 1978 Jan;73(1):180–191. [PubMed] [Google Scholar]
  39. Robbins E., Morrill G. A. Oxygen uptake during the HeLa cell life cycle and its correlation with macromolecular synthesis. J Cell Biol. 1969 Dec;43(3):629–633. doi: 10.1083/jcb.43.3.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Stratford I. J., Adams G. E. Effect of hyperthermia on differential cytotoxicity of a hypoxic cell radiosensitizer, Ro-07-0582, on mammalian cells in vitro. Br J Cancer. 1977 Mar;35(3):307–313. doi: 10.1038/bjc.1977.44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Stratford I. J., Gray P. Some factors affecting the specific toxicity of misonidazole towards hypoxic mammalian cells. Br J Cancer Suppl. 1978 Jun;3:129–131. [PMC free article] [PubMed] [Google Scholar]
  42. Stratford I. J., Williamson C., Adams G. E. Combination studies with misonidazole and a cis-platinum complex: cytotoxicity and radiosensitization in vitro. Br J Cancer. 1980 Apr;41(4):517–522. doi: 10.1038/bjc.1980.93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. 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]
  44. 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]
  45. 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]
  46. 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]

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