Potency and specificity of CGS-16949A as an aromatase inhibitor.
Inhibitors of aromatase are useful for treatment of estrogen-dependent breast cancer and as probes for study of normal physiology. Inhibitors of this enzyme with more favorable properties are necessary since the most extensively utilized inhibitor, aminoglutethimide, lacks specificity and causes frequent side effects. The present study compared the potency and specificity of a new aromatase inhibitor, CGS-16949A, with that of aminoglutethimide in a variety of in vitro enzyme preparations. CGS-16949A blocked aromatase by 50% in human breast cancer homogenates, live breast cancer cells, human placental microsomes and porcine ovarian microsomes at concentrations of 0.008 to 0.02 microM. In contrast, concentrations of 10-25 microM of aminoglutethimide were required to inhibit aromatase similarly in these tissues. For human placental microsomes, the Ki for CGS 16949A was 0.17 nM and for aminoglutethimide, 0.54 microM. Preincubation studies indicated that CGS-16949A acts by a competitive inhibitory mechanism and not by "suicide inhibitory" properties. With respect to specificity, CGS-16949A had no effect on cholesterol side-chain cleavage activity in rat testicular mitochondria. A 54% reduction in enzyme activity was observed in adrenal mitochondria but only at concentrations five orders of magnitude higher (i.e. 100 microM) than required to inhibit aromatase. In contrast, 10 microM concentrations of aminoglutethimide blocked cholesterol side-chain cleavage activity in rat testicular and adrenal mitochondria by 67 and 91%, respectively. These data suggest that CGS-16949A has favorable properties as a specific and potent aromatase inhibitor.
Santen
R J
RJ
Department of Medicine, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17033.
Langecker
P
P
Santner
S J
SJ
Sikka
S
S
Rajfer
J
J
Swerdloff
R
R
D000818:Animals; D001141:Aromatase / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017316:Fadrozole; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology*; D010053:Ovary / Q000187:drug effects / Q000201:enzymology*; D010920:Placenta / Q000187:drug effects / Q000201:enzymology*; D013552:Swine
D004791:Enzyme Inhibitors; D007093:Imidazoles; D009570:Nitriles; D001141:Aromatase; D017316:Fadrozole