EFFECTS OF ANTHRACYCLINES ON OXYGENATED AND HYPOXIC TUMOR-CELLS

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (1) , 54-59
Abstract
The cytotoxic effects of anthracyclines and other chemotherapeutic agents were examined in normally aerated and hypoxic [mouse] Sarcoma 180 and [mouse] EMT6 [mammary] tumor cells in vitro. Adriamycin, daunomycin and mitomycin C were selectively toxic to hypoxic Sarcoma 180 cells. In general, the augmented sensitivity was not the result of an increase in susceptibility of oxygen-deprived cells toward antitumor agents. 1,3-Bis(2-chloroethyl)-1-nitrosourea, for example, exhibited equal cytotoxicity toward normally aerated and hypoxic cells; streptonigrin was selectively toxic toward normally aerated cells. The cellular levels of [3H]daunomycin in both Sarcoma 180 and EMT6 cells were not different under the 2 conditions of oxygenation; no greater production of the alcohol or aglycone metabolites of daunomycin occurred in hypoxic cells, compared with their normally aerated counterparts. Analysis of cellular pellets for residual drug remaining after exhaustive extraction showed no significant difference between normally aerated and hypoxic cells. The effects of reoxygenation of hypoxic cells on their sensitivity to mitomycin C and to adriamycin were studied in Sarcoma 180 and EMT6 cells. The enhanced efficacy of mitomycin C as a cytotoxic agent observed under hypoxia was reversed after a 2-h reoxygenation. In contrast, the augmented toxicity of adriamycin toward hypoxic cells was not reversible in either cell line after 2 or 4 h of reoxygenation. The results suggest that neither the formation of a reactive oxygen species nor direct involvement of an alkylating agent generated by drug metabolism is an obligatory step in the cytotoxic action of these anthracyclines.