Cancer Chemotherapy and Pharmacology

, Volume 30, Issue 4, pp 277–280

Effect of etoposide, carmustine, vincristine, 5-fluorouracil, or methotrexate on radiobiologically oxic and hypoxic cells in a C3H mouse mammary carcinoma in situ

  • Cai Grau
  • Jens Overgaard
Original Articles Tumor Hypoxia, Multi-Drug Chemotherapy, Radiation

Summary

The effect of etoposide (VP16), carmustine (BCNU), vincristine (VCR), methotrexate (MTX), and 5-fluorouracil (5-FU) on the oxic and hypoxic cells in a C3H mammary carcinoma in CDF1 mice was investigated using an in situ local-tumor-control (TCD50) assay. The surviving fraction (SF) was calculated from the size of the radiation dose needed to inactivate the surviving tumor cells in drug-treated tumors relative to untreated controls. Preferential drug cytotoxicity towards oxic and hypoxic cells was evaluated from the difference in the response to irradiation under ambient and clamped conditions, respectively. Three drugs caused a significant (P<0.05) reduction in the survival of hypoxic cells, the SFs being 0.31 (VP-16), 0.13 (BCNU) and 0.16 (VCR). VCR was also toxic towards oxic cells (SF, 0.17), whereas VP16 and BCNU had no significant effect on these cells (SF, 0.5 and 0.76, respectively). Two drugs produced significant killing of cells in the oxic compartment: 5-FU (SF, 0.10) and MTX (SF, 0.22); these two drugs had no effect on hypoxic cells (SF, 0.78 and 1.11, respectively).

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References

  1. 1.
    Brown JM, Lemmon MJ (1990) Potentiation by the hypoxic cytotoxin SR 4233 of cell killing produced by fractionated irradiation of mouse tumors. Cancer Res 50: 7745–7749Google Scholar
  2. 2.
    Chaplin DJ, Durand RE, Stratford IJ, Jenkins TC (1986) The radiosensitizing and toxic effects of RSU-1069 on hypoxic cells in a murine tumor. Int J Radiat Oncol Biol Phys 12: 1091–1095Google Scholar
  3. 3.
    Durand RE (1990) Cisplatin and CCNU synergism in spheroid cell subpopulations. Br J Cancer 62: 947–953Google Scholar
  4. 4.
    Durand RE (1991) The influence of microenvironmental factors on the activity of radiation and drugs. Int J Radiat Oncol Biol Phys 20: 253–258Google Scholar
  5. 5.
    Gatenby RA, Kessler HB, Rosenblum JS, Coia LR, Moldofsky PJ, Hartz WH, Broder GJ (1988) Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int J Radiat Oncol Biol Phys 14: 831–838Google Scholar
  6. 6.
    Grau C, Overgaard J (1988) Effect of cancer chemotherapy on the hypoxic fraction of a solid tumor measured using a local tumor control assay. Radiother Oncol 13: 301–309Google Scholar
  7. 7.
    Grau C, Overgaard J (1990) The influence of radiation dose on the magnitude and kinetics of reoxygenation in a C3H mammary carcinoma. Radiat Res 122: 309–315Google Scholar
  8. 8.
    Grau C, Overgaard J (1991) Radiosensitizing and cytotoxic properties of mitomycin C in a C3H mouse mammary carcinoma in vivo. Int J Radiat Oncol Biol Phys 20: 265–269Google Scholar
  9. 9.
    Grau C, Bentzen SM, Overgaard J (1990) Cytotoxic effect of misonidazole and cyclophosphamide on aerobic and hypoxic cells in a C3H mammary carcinoma in vivo. Br J Cancer 61: 61–64Google Scholar
  10. 10.
    Grau C, Horsman MR, Overgaard J (1992) Influence of carboxyhemoglobin level on tumor growth, blood flow, and radiation response in an experimental model. Int J Radiat Oncol Biol Phys (in press)Google Scholar
  11. 11.
    Hill RP, Stanley JA (1975) The response of hypoxic B16 melanoma cells to in vivo treatment with chemotherapeutic agents. Cancer Res 35: 1147–1153Google Scholar
  12. 12.
    Moulder JE, Rockwell S (1984) Hypoxic fractions of solid tumours. Int J Radiat Oncol Biol Phys 10: 695–712Google Scholar
  13. 13.
    Overgaard J, Matsui M, Lindegaard JC, Grau C, Zachariae C, Johansen IM, Maase H von der, Nielsen OS (1987) Relationship between tumor growth delay and modification of local-control probability of various treatments given as an adjuvant to irradiation. In: Kallman RF (ed) Rodent tumor models in experimental cancer therapy. Pergamon, New York, pp 128–132Google Scholar
  14. 14.
    Overgaard J, Grau C, Lindegaard JC, Horsman MR (1990) The potential of using hyperthermia to eliminate radioresistant hypoxic cells. Radiother Oncol 20 [Suppl 1]: 113–116Google Scholar
  15. 15.
    Overgaard J, Radacic M, Grau C (1991) Interaction between hyperthermia andcis-diamminedichloroplatinum(II) alone or combined with radiation in a C3H mammary carcinoma in vivo. Cancer Res 51: 707–711Google Scholar
  16. 16.
    Suit HD, Shalek RJ, Wette R (1965) Radiation response of a C3H mouse mammary carcinoma evaluated in terms of cellular radiation sensitivity. In: Cellular radiation biology. Williams & Wilkins, Baltimore, pp 514–530Google Scholar
  17. 17.
    Tannock IF (1987) Toxicity of 5-fluorouracil for aerobic and hypoxic cells in two murine tumours. Cancer Chemother Pharmacol 19: 53–56Google Scholar
  18. 18.
    Tannock IF, Guttman P (1981) Response of Chinese hamster ovary cells to anti-cancer drugs under aerobic and hypoxic conditions. Br J Cancer 43: 245–248Google Scholar
  19. 19.
    Teicher BA, Lazo JS, Sartorelli AC (1981) Classification of antineoplastic agents by their selective toxicities toward oxygenated and hypoxic cells. Cancer Res 41: 73–81Google Scholar
  20. 20.
    Teicher BA, Holden SA, Rose CM (1985) Effect of oxygen on the cytotoxicity and antitumor activity of etoposide. J Natl Cancer Inst 75: 1129–1133Google Scholar
  21. 21.
    Teicher BA, Bernal SD, Holden SA, Cathcart KNS (1988) Effect of fluosol-DA/carbogen on etoposide/alkylating agent antitumor activity. Cancer Chemother Pharmacol 21: 281–285Google Scholar
  22. 22.
    Teicher BA, Holden SA, Al-Achi A, Herman TS (1990) Classification of antineoplastic treatments by their differential toxicity toward putative oxygenated and hypoxic tumor subpopulations in vivo in the FSaIIC murine fibrosarcoma. Cancer Res 50: 3339–3344Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Cai Grau
    • 1
  • Jens Overgaard
    • 1
  1. 1.Department of Experimental Clinical Oncology, RadiumstationenDanish Cancer SocietyAarhus C.Denmark

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