Prolactin release-inhibitory effects of progesterone, megestrol acetate, and mifepristone (RU 38486) by cultured rat pituitary tumor cells.
The prolactin (PRL) release-inhibitory effects of progesterone, dexamethasone, megestrol acetate, and mifepristone (RU 38486) were studied in cultured pituitary tumor cells prepared from the 7315a and 7315b tumor. Both tumors contain similar numbers of estrogen and progesterone receptors, while only the 7315a tumor also has glucocorticoid receptors. PRL release by the 7315a tumor was stimulated by low concentrations of dexamethasone (10(-10)-10(-9) M) and was inhibited in a dose-dependent manner by higher concentrations (-86% by 10(-7) M). In contrast only 10(-6) and 10(-5) M dexamethasone inhibited PRL release by the 7315b cells by 14 and 24%, respectively. Progesterone caused a dose-dependent inhibition of PRL release, which was similar in the 7315a and b tumor cells. Progesterone (10(-9) M) inhibited PRL release by 62% and this inhibition was completely prevented by 100 nM estradiol, which was stimulatory by itself (+48%). Mifepristone inhibited PRL release by both tumors in a dose-dependent manner, but more powerfully in the 7315a tumor; 10(-6) M concentrations of the compound inhibited PRL release by 52% in the 7315a and by 26% in the 7315b tumor cells. Megestrol acetate inhibited PRL release in both tumors in a dose-dependent manner, but more powerfully in the 7315b tumor; a 10(-8) M concentration of the compound inhibited PRL release by 54% in the 7315b tumor and by 14% in the 7315a tumor. In the 7315a tumor 10(-9) M megestrol acetate even stimulated PRL release, suggesting a dexamethasone-like glucocorticoid effect of the drug on this tumor. Thereafter the interaction of mifepristone and megestrol acetate on PRL release was investigated. In the 7315a tumor cells different combinations of both drugs neutralized each other's inhibitory effects on PRL release, while both drugs had additional inhibitory effects on PRL release by 7315b tumor cells. Changes in PRL release by the cultured pituitary tumor cells were in all instances closely correlated with changes in the PRL content, the protein content, and the DNA content of the tumor cells. This suggests that the inhibitory effect of the compounds studied on PRL release is paralleled by an inhibitory effect on the number of pituitary tumor cells. These studies show the importance of the presence of glucocorticoid receptors in the effectiveness and mechanism of action of the antitumor effects of megestrol acetate and mifepristone.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology*; D008535:Megestrol / Q000031:analogs & derivatives* / Q000494:pharmacology; D019290:Megestrol Acetate; D015735:Mifepristone; D010911:Pituitary Neoplasms / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology*; D011388:Prolactin / Q000378:metabolism*; D051381:Rats; D011915:Rats, Inbred BUF; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology
D004963:Estrenes; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D013629:Tamoxifen; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; D003907:Dexamethasone; D011388:Prolactin; D008535:Megestrol; D019290:Megestrol Acetate