The effect of fluocinolone acetonide and 12-O-tetradecanoyl-phorbol-13-acetate on the binding and biological activity of epidermal growth factor in rat fibroblasts

Synthetic glucocorticoids such as fluocinolone acetonide (FA) have been shown to be potent inhibitors of phorbol ester-mediated tumor promotion. When Rat-1 cells were incubated with FA the cells showed an increased capacity to bind [¹²⁵I]-epidermal growth factor (EGF) to surface receptors. A partial reversal of the ability of the phorbol ester tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate to reduce EGF binding to the class of high affinity receptors occurred following pre-exposure of cells to FA. The increased binding of EGF induced by FA resulted in a faster rate of degradation of EGF from the culture medium and reversed the inhibition of degradation caused by TPA. When EGF was present at low concentrations (<1 ng/ml), at which level FA was effective in increasing EGF degradation, FA-treated cells displayed a decreased induction of ornithine decarboxylase (ODC) activity and DNA synthesis. At higher EGF concentrations, the same level of ODC activity and DNA synthesis occurred in the presence or absence of FA, although some differences in the rates of induction were noted. These results support the hypothesis that the hyperplasia-inhibiting ability of glucocor-ticoid antipromoters may act by modulating EGF levels in the extracellular environment. However, our data also indicate that these antipromoters may act through other cellular mechanisms as well.