ENHANCEMENT BY HYPERTHERMIA OF THE INVITRO CYTO-TOXICITY OF MITOMYCIN-C TOWARD HYPOXIC TUMOR-CELLS

Google Scholar
  • 1 January 1981
    • journal article
    • research article
    • Vol. 41  (3) , 1096-1099
Abstract
Mitomycin C and hyperthermia are toxic to chronically hypoxic [mouse mammary] tumor EMT6 cells. Combinations of this drug and heat were tested in vitro in normally aerated and chronically hypoxic EMT6 cells to establish whether greater than additive cytotoxicity could be achieved by combined treatment. Cell survival was measured at 4 concentrations of mitomycin C (0.01, 0.1, 1.0 and 10 .mu.M) at 37.degree. or at elevated temperatures (41, 42 and 43.degree.) for durations of 1, 2, 3 and 6 h. At 42.degree. C, exposure to mitomycin C for 3 and 6 h produced a 2- to 3-fold increase in hypoxic tumor cell kill at all drug concentrations over that expected for strict additivity. A 15-fold enhancement in the kill of hypoxic tumor cells was obtained at 1.0 and 10 .mu.M mitocmyin C at 43.degree. C for 6 h of exposure. Under most conditions, additivity was observed for the antibiotic and heat in oxygenated cells, except at 43.degree. with 0.01 and 0.1 .mu.M mitomycin C following 3 and 6 h of treatment, conditions under which a 5- to 10-fold potentiation of tumor cell kill was obtained. The rate of formation of reactive metabolites from mitomycin C under anaerobic conditions in EMT6 cell-free preparations was measured. A 30-50% increase in alkylating activity was observed at elevated temperatures; the enhanced cytotoxicity of mitomycin C with heat toward hypoxic cells may, in part, be due to an increase in activation of the drug.