OXYGEN RADICAL DETOXIFICATION ENZYMES IN DOXORUBICIN-SENSITIVE AND DOXORUBICIN-RESISTANT P388 MURINE LEUKEMIA-CELLS

Google Scholar
  • 1 January 1984
    • journal article
    • research article
    • Vol. 44  (5) , 1976-1980
Abstract
One of the proposed mechanisams for the cytotoxic effects of anthracycline compounds suggests that the effect is mediated through the formation of intracellular superoxide radicals. Possibly doxorubicin resistance is associated with increased intracellular enzyme capacity to convert these superoxide radicals to inactive metabolites. The relative activities were measured of superoxide dismutase, glutathione peroxidase, and catalase in P388 mouse leukemia cells and in a doxorubicin-resistant subline. Since oxygen-reactive metabolites also play a role in mediating the cytotoxicity of ionizing radiation, the radiosensitivity of both cell lines was also studied. No significant differences in superoxide dismutase activity between these cell lines was observed, indicating that they have a similar capacity to convert superoxide anion radicals to H2O2. P388 cells that are resistant to doxorubicin have 1.5 times the glutathione content and 1.5 times the activity of glutathione peroxidase measured in drug-sensitive P388 cells. However, incubation with 1-chloro-2,4-dinitrobenzene, which covalently binds glutathione, had no effect on the sensitivity of either cell line to doxorubicin. Measured catalase activity in drug-resistant P388 cells was 1/3 of the activity measured in doxorubicin-sensitive P388 cells. The activity of this enzyme was much higher than that of glutathione peroxidase in terms of H2O2 deactivation in both cell lines. It is therefore unlikely that doxorubicin-resistant P388 cells have an increased ability to detoxify reactive oxygen metabolites when compared to drug-sensitive cells. Doxorubicin-resistant P388 cells were significantly more sensitive to X-irradiation than were drug-sensitive P388 cells. Possibly, the difference in catalase activity in these cell lines may be associated with the observed differences in radiosensitivity.