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In Vitro

, Volume 15, Issue 9, pp 685–690 | Cite as

Cytotoxicity of glucose analogues in V79 multicell spheroids

  • Rajagopalan Sridhar
  • Eric C. Stroude
  • W. Rodger Inch
Article

Summary

2-Deoxy-d-glucose (2DG) and 5-thio-d-glucose (5TG) are glucose antimetabolites that are known to be selectively toxic to hypoxic cells grown as single cells or as monolayer cultures. These analogues were toxic to Chinese hamster V79 cells grown as multicell spheroids even under aerobic conditions. When spheroids, 500- to 600-μm diameter, were exposed to 7.5mm of these chemicals for 3 days, the number of clonogenic cells per spheroid dropped to 50% for 5-thio-d-glucose and 20% for 2-deoxy-d-glucose, relative to control values. Survivals were reduced to less than 1% when the experiment was repeated in glucose-free medium. Scanning electron photomicrographs of spheroids treated with 7.5mm of either analogue showed extensive damage to the outer cells. The cell killing observed was much more than could be predicted on the basis of the hypoxic fraction known to be present in these spheroids. The crowded tumor-like environment may make the cells vulnerable to the cytotoxic action of glucose analogues and other glycolytic inhibitors.

Key words

cytotoxicity glucose analogues cancer chemotherapy spheroids 

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References

  1. 1.
    Gray, L. H., A. O. Conger, M. Ebert, S. Hornsey, and O. C. A. Scott. 1973. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br. J. Radiol. 26: 638–648.Google Scholar
  2. 2.
    Thomlinson, R. H., and L. H. Gray. 1955. The histological structure of some human lung cancers and the possible implications of radiotherapy. Br. J. Cancer 9: 539–549.PubMedGoogle Scholar
  3. 3.
    Begg, A. C., P. W. Sheldon, and J. L. Foster. 1974. Demonstration of radiosensitization of hypoxic cells in solid tumors by metronidazole. Br. J. Radiol. 47: 399–404.PubMedCrossRefGoogle Scholar
  4. 4.
    Brown, J. M. 1975. Selective radiosensitization of the hypoxic cells of mouse tumors with the nitro-imidazoles, metronidazole and Ro-07-0582. Radiat. Res. 64: 633–647.PubMedCrossRefGoogle Scholar
  5. 5.
    Inch, W. R., J. A. McCredie, M. J. Haynes, and R. M. Sutherland. 1977. Effect of metronidazole on the C3H/HeJ mouse and the growth of the C3HBA mammary adenocarcinoma. Growth 41: 15–23.PubMedGoogle Scholar
  6. 6.
    Urtasun, R., P. Band, J. D. Chapman, M. L. Feldstein, B. Mielki, and C. Fryer. 1976. Radiation and high dose metronidazole in supretentorial glioblastomas. N. Engl. J. Med. 294: 1364–1366.PubMedCrossRefGoogle Scholar
  7. 7.
    Foster, J. L., P. J. Conroy, A. J. Searle, and R. L. Wilson. 1976. Metronidazole (Flagyl): Characterization as a cytotoxic drug specific for hypoxic tumor cells. Br. J. Cancer 33: 485–490.PubMedGoogle Scholar
  8. 8.
    Mohindra, J. K., and A. M. Rauth. 1976. Increased cell killing by metronidazole and nitrofurazone of hypoxic compared to aerobic mammalian cells. Cancer Res. 36: 930–936.PubMedGoogle Scholar
  9. 10.
    Song, C. W., J. J. Clement, and S. H. Levitt. 1976. Preferential cytotoxicity of 5-thio-d-glucose against hypoxic tumor cells. J. Nat. Cancer Inst. 57: 603–605.PubMedGoogle Scholar
  10. 11.
    Song, C. W., J. J. Clement, and S. H. Levitt. 1977. Cytotoxic and radiosensitizing effects of 5-thio-d-glucose on hypoxic cells. Radiology 123: 201–205.PubMedGoogle Scholar
  11. 12.
    Sridhar, R., C. Koch, and R. M. Sutherland. 1976. Cytotoxicity of two nitroimidazole radiosensitizers in anin vitro tumor model. Int. J. Radiat. Oncol. Biol. Phys. 1: 1149–1157.PubMedGoogle Scholar
  12. 13.
    Sridhar, R.. 1977. Selective toxicity of 2-deoxy-d-glucose towards hypoxic mammalian cells (abstr.). Fed. Proc. 36: 336.Google Scholar
  13. 14.
    Sutherland, R. M. 1974. Selective chemotherapy of non-cycling cells in anin vitro tumor model. Cancer Res. 34: 3501–3503.PubMedGoogle Scholar
  14. 15.
    Chen, M., and R. L. Whistler. 1975. Action of 5-thio-d-glucose and its l-phosphate with hexokinase and phosphoglucomutase. Arch. Biochem. Biophys. 169: 392–396.PubMedCrossRefGoogle Scholar
  15. 16.
    Walker, D. G. 1966. The nature and function of hexokinase in animal tissue. In: P. N. Campbell, and G. D. Greville (Ed.),Essays in Biochemistry, Vol. 2. Academic Press, New York, pp. 33–67.Google Scholar
  16. 17.
    Aisenberg, A. C. 1961.Glycolysis and Respiration of Tumors. Academic Press, London.Google Scholar
  17. 18.
    Ball, H. A., A. N. Wick, and C. Sanders. 1957. Influence of glucose antimetabolites on the Walker tumor. Cancer Res. 17: 235–239.PubMedGoogle Scholar
  18. 19.
    Brown, J. 1962. Effect of 2-deoxyglucose on carbohydrate metabolism: Review of the literature and studies in the rat. Metabolism 11: 1098–1112.PubMedGoogle Scholar
  19. 20.
    Laszlo, J., B. Landau, K. Wight, and D. Burk. 1958. The effect of glucose analogues on the metabolism of human leukemic cells. J. Nat. Cancer Inst. 21: 475–483.PubMedGoogle Scholar
  20. 21.
    Laszlo, J., S. R. Humphreys and A. Goldin. 1960. Effects of glucose analogues (2-deoxy-d-glucose, 2-deoxy-d-galactose) on experimental tumors. J. Nat. Cancer Inst. 24: 267–281.PubMedGoogle Scholar
  21. 22.
    Sutherland, R. M., and R. E. Durand. 1976. Radiation response of multicell spheroids—anin vitro tumor model. Curr. Top. Radiat. Res. 11: 87–139.Google Scholar
  22. 23.
    Sutherland, R. M., J. A. McCredie, and W. R. Inch. 1971. Growth of multicell spheroids in tissue culture as a model of nodular carcinoma. J. Nat. Cancer Inst. 46: 113–120.PubMedGoogle Scholar
  23. 24.
    Kim, S. H., J. H. Kim, and E. W. Hahn. 1978. Selective potentiation of hyperthermic killing of hypoxic cells by 5-thio-d-glucose. Cancer Res. 38: 2935–2938.PubMedGoogle Scholar
  24. 25.
    Franko, A. J. 1976. Oxygen diffusion in the multicell spheroidin vitro tumor model. Effects on cell survival and radiation response. Ph.D thesis, University of Western Ontario, London, Ontario.Google Scholar
  25. 26.
    Myers, M. W., and A. C. Sartorelli. 1975. Effects of low concentrations of 2-deoxy-d-glucose on the growth, surface architecture, and glycoprotein metabolism of P388 lymphoma cells. Biochem. Biophys. Res. Commun. 63: 164–171.PubMedCrossRefGoogle Scholar
  26. 27.
    Wassenaar, W., C. H. Tator, and H. P. Batty. 1975. Glucose and analogues as potential diagnostic tracers for brain tumors. Cancer Res. 35: 785–790.PubMedGoogle Scholar

Copyright information

© Tissue Culture Association 1979

Authors and Affiliations

  • Rajagopalan Sridhar
    • 1
  • Eric C. Stroude
    • 1
  • W. Rodger Inch
    • 1
  1. 1.The Ontario Cancer Treatment and Research Foundation, London Clinic, Experimental Oncology GroupVictoria HospitalLondonCanada

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