Studies on the glucocorticoid-receptor blocking action of RU 38486 in cultured ACTH-secreting human pituitary tumour cells and normal rat pituitary cells.

Abstract

The glucocorticoid-receptor blocking actions of RU 38486, a new compound with anti-progesterone activity, have been investigated in cultured human ACTH-secreting pituitary tumour cells and normal rat pituitary cells. Pre-incubation of human pituitary tumour cells for 24 h with RU 38486 (1 microM) did not influence basal or CRF-stimulated ACTH release. RU 38486 (100 nM-1 microM) significantly overcame or prevented the dexamethasone (100 nM-1 microM)-induced inhibition of CRF-stimulated ACTH release by the cultured tumour cells prepared from 2 patients with Cushing's disease. The tumour cells of a third patient were insensitive to CRF. Pre-incubation for 24 h with 1 microM RU 38486 facilitated CRF-stimulated ACTH release significantly. Studies with cultured normal rat pituitary cells showed that the inhibiting effect of 24 h pre-incubation with 10 and 50 nM dexamethasone on CRF-stimulated ACTH release could be acutely (measured over 4 h) overruled in a dose-dependent way by RU 38486 (100 nM, 1 and 10 microM), while pre-incubation for 24 h of these cells with RU 38486 (100 nM and 1 microM) significantly attenuated the acute inhibiting effect of 1 microM dexamethasone on CRF-stimulated ACTH-release. The results of these in vitro experiments are discussed against the background of the possible therapeutic use RU 38486 in patients with Cushing's syndrome in order to block the deleterious effects of high circulating cortisol concentrations.