Endocrine effects of Trilostane: in vitro and in vivo studies.
Trilostane (4-alpha-5-epoxy-17 beta-hydroxy-3-oxo-5-alpha-androstan-2-carbonitrile) is a modified steroidal molecule. In vitro and in vivo studies in rats have shown that it inhibits adrenal, ovarian and placental steroid synthesis. It seems to act by exerting a selective blockade on 3 beta-hydroxysteroid dehydrogenase. In this study, we investigated whether this molecule interacts with hormone receptors for estrogen, androgen or progesterone. We also tried to demonstrate the effect which Trilostane may have on cellular cultures of human mammary carcinoma (MCF-7 Evsa-T). We also studied hormonal modifications in a series of 12 patients treated with different doses of Trilostane, since this drug is supposed to inhibit the production by the adrenal glands of mineralocorticoids, of glucocorticoids and of the precursors of estrogens. Our results indicate that Trilostane does not react with any of the main hormonal sex steroid receptors, nor does it interfere with cultures of human mammary cancer cells either containing estrogen receptors and therefore allegedly hormone-dependent (MCF-7 line), or estrogen receptor-negative cells, presumably independent of hormonal manipulations (Evsa-T cell line). Finally, endocrine studies on postmenopausal women with advanced breast cancer show that Trilostane significantly reduces the plasma levels of estrone and of its major androgen precursor (androstenedione). However, the latter inhibition is no different from that exerted by hydrocortisone acetate administered alone at a dose of 40 mg/day. The results of clinical trials comparing hydrocortisone alone with hydrocortisone plus Trilostane are awaited.
Tueni
E
E
Service de Médicine, Institut Jules Bordet, Centre des Tumeurs de l'Université Libre de Bruxelles, Belgium.
Devleeschouwer
N
N
Leclercq
G
G
Nijs
M
M
Coune
A
A
Vermeulen
A
A
Paridaens
R
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006728:Hormones / Q000097:blood*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; D006728:Hormones; D011956:Receptors, Cell Surface; D013196:Dihydrotestosterone; C009954:trilostane; D006854:Hydrocortisone