title: An in vitro method to determine the selective inhibition of estrogen biosynthesis by aromatase inhibitors.
abstract: Potency and selectivity of aromatase inhibition are parameters which ultimately influence the therapeutic efficacy of aromatase inhibitors. This report describes an in vitro model which allows an assessment of the selectivity with which aromatase inhibitors inhibit estrogen biosynthesis. Estrogen production was stimulated by incubating adult female hamster ovarian tissue with ovine LH. The production rates of estrogens (E), testosterone (T) and progesterone (P) were determined using radioimmunoassays to measure the amount of these steroids released into the incubation medium over a 4-hour incubation period. The selectivity of aromatase inhibition was assessed by determining the IC50S with which each inhibitor inhibited the production of E (end product), T (immediate precursor of E) and P (early precursor of E). Selectivity was studied for each of the 4 aromatase inhibitors, CGS 16949A (a new non-steroidal compound), 4-OH-androstenedione, aminoglutethimide and testolactone. CGS 16949A was the most potent of the four, followed by 4-OH-androstenedione, aminoglutethimide and testolactone. As far as selectivity was concerned, both CGS 16949A and 4-OH-androstenedione selectively inhibited aromatase judging from the IC50s for E and P production (CGS 16949A: IC50 for E & P = 0.03 & 160 microM, resp.; 4-OH-androstenedione: IC50 for E & P = 0.88 & greater than or equal to 330 microM, resp.). Aminoglutethimide was the least selective inhibitor of aromatase (IC50 for E & P = 13 & 60 microM, resp.). For testolactone, the least potent of the four (IC50 for E = 130 microM), no conclusive data were obtained concerning the selectivity of aromatase inhibition. Thus a simple, effective and reproducible method is described for assessing the selectivity with which aromatase inhibitors inhibit aromatase.
authors.affiliation: Research Department, Ciba-Geigy Ltd., Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Häusler
authors.forename: L
authors.initials: L
authors.lastname: Schenkel
authors.forename: C
authors.initials: C
authors.lastname: Krähenbühl
authors.forename: G
authors.initials: G
authors.lastname: Monnet
authors.forename: A S
authors.initials: AS
authors.lastname: Bhatnagar
mesh_terms: D000616:Aminoglutethimide / Q000494:pharmacology; D000735:Androstenedione / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors; D006224:Cricetinae; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000096:biosynthesis*; D004971:Estrus; D017316:Fadrozole; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D007986:Luteinizing Hormone / Q000494:pharmacology; D008647:Mesocricetus; D009570:Nitriles / Q000494:pharmacology; D010053:Ovary / Q000187:drug effects / Q000378:metabolism*; D011374:Progesterone / Q000096:biosynthesis; D013738:Testolactone / Q000494:pharmacology; D013739:Testosterone / Q000096:biosynthesis
chemical_list: D047072:Aromatase Inhibitors; D004965:Estrogen Antagonists; D004967:Estrogens; D007093:Imidazoles; D009570:Nitriles; D000616:Aminoglutethimide; D013739:Testosterone; D000735:Androstenedione; D011374:Progesterone; D013738:Testolactone; D007986:Luteinizing Hormone; D017316:Fadrozole; C014594:formestane