Comparison of in vitro exemestane activity versus other antiaromatase agents.
Anastrozole, letrozole, and exemestane are the most selective and potent oral antiaromatase agents currently available. However, in vitro and in vivo studies comparing these agents are lacking. Anastrozole and letrozole are reversible, competitive nonsteroidal type II inhibitors, whereas exemestane is an irreversible steroidal type I inactivator. The study was conducted to determine the impact of this characteristic on in vitro residual aromatase activity and protein levels after incubation of JEG-3 cells with aminoglutethimide (a type II inhibitor), anastrozole, exemestane, or letrozole. Aromatase activity was measured after various incubation times with each antiaromatase agent at a concentration 10 times higher than IC50 (concentration giving 50% inhibition). Only exemestane induced a residual inhibition of aromatase activity after its removal, without any change in the aromatase protein level. Aromatase activity increased after preincubation of JEG-3 cells with either aminoglutethimide or anastrozole without any change in the aromatase protein level. The aromatase protein level increased rapidly when cells were incubated with letrozole and aromatase activity inhibition disappeared immediately after removal of the drug. The breakthrough effects in aromatase activity or protein levels observed after treatment with reversible inhibitors may be a factor in therapeutic failure with these agents. These results suggest a possible advantage for exemestane because it is the only clinically available oral irreversible aromatase inactivator.
Soudon
J
J
Pharmacell, Paris, France. pharm2@jupiter.chu-stlouis.fr
D000616:Aminoglutethimide / Q000494:pharmacology; D000077384:Anastrozole; D000730:Androstadienes / Q000494:pharmacology*; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002822:Choriocarcinoma / Q000473:pathology*; D005260:Female; D006801:Humans; D009570:Nitriles / Q000008:administration & dosage; D014230:Triazoles / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
D000730:Androstadienes; D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000616:Aminoglutethimide; D000077384:Anastrozole; C056516:exemestane