Comparison of the actions of RU 38486 and megestrol acetate in the model of a transplantable adrenocorticotropin- and prolactin-secreting rat pituitary tumor.
The effects of the progesterone antagonist RU 38486 and the progesterone agonist megestrol acetate on the growth of the estrogen-progesterone receptor-positive transplantable adrenocorticotropin (ACTH)/prolactin-secreting rat pituitary tumor 7315a were examined. RU 38486 (2.5 mg/kg/day) for 30 days significantly inhibited tumor size, tumor weight, and the plasma prolactin and ACTH concentrations, while the same dose of megestrol acetate only inhibited pituitary tumor weight. Megestrol acetate inhibited both the release and total ACTH content of the anterior pituitary gland, while RU 38486 increased both the release and the total ACTH content. Studies with ACTH secretion by cultured normal rat pituitary cells showed that megestrol acetate (1 microM) did not affect corticotropin-releasing factor (CRF)-stimulated ACTH release after 4-hr exposure, but inhibited CRF-stimulated ACTH release by 50% after 24-hr preincubation. The glucocorticoid-like effect of 1 microM megestrol acetate in this model is similar to that exerted by 10 nM dexamethasone. Acute exposure or preincubation of rat pituitary cells with RU 38486 (1 microM) did not influence CRF-stimulated ACTH release, while preincubation for 24 hr revealed a dose-dependent reversing effect of RU 38486 on dexamethasone-induced inhibition of CRF-stimulated ACTH release. In this model, 1 microM RU 38486 completely overcame the effect of 10 nM dexamethasone. Megestrol acetate and RU 38486 have inhibitory effects on the growth of the 7315a tumor. They differ both with regard to their effects on the progesterone and the glucocorticoid receptor, with megestrol acetate exerting an agonistic and RU 38486 an antagonistic action.
Lamberts
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Uitterlinden
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Bons
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EG
Verleun
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D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D004963:Estrenes / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D008535:Megestrol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019290:Megestrol Acetate; D015735:Mifepristone; D009368:Neoplasm Transplantation; D009929:Organ Size / Q000187:drug effects; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011388:Prolactin / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000187:drug effects
D004963:Estrenes; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D008535:Megestrol; D019290:Megestrol Acetate