Antagonism of glucocorticoid induction of Epstein-Barr virus early antigens by different steroids in Daudi lymphoma cells

Four antiglucocorticoids, RU38486, RU5020, RU25055 and progesterone were found to antagonize the induction of latent Epstein-Barr virus (EBV) information by dexamethasone. The dose response studies show that the antagonization was more prominent with the synthetic steroids than with the natural hormone. Specific binding characteristics of dexamethasone measured in whole cells indicate the presence of glucocorticoid receptors. Total cellular receptor contents deduced from binding data give values similar to those reported for B-lymphoblasts. Competition experiments between dexamethasone and RU38436 strongly suggest that RU38486 binds to two distinct sites in the whole cell; one is the glucocorticoid receptor but the nature of the other site is unknown. Inhibition by antiglucocorticoids differs from antagonism by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) since the latter does not compete for any sites interacting with RU38486.     

Steroid metabolism in normal and transformed liver cells. Relation with glucocorticoid antagonism

The metabolism of the potent antagonist RU38486 has been studied in cultured liver cells and in two hepatoma cell lines. In the liver cells, this steroid undergoes a rapid degradation, whereas in hepatoma cells grown in similar conditions only a minor degradation occurs. Moreover the rate of degradation is much higher for the antagonist steroid than for the agonist steroid tested, dexamethasone. The high antiglucocorticoid potency and the relative instability of the RU38486 molecule are very important to define its different effects and its mechanism of action in liver and in liver derived tumor cells. RU38486 may represent a useful drug in cancerotherapy.