Abstract：
:Use of steroid biosynthesis inhibitors to suppress estrogen production is a logical strategy in the treatment of women with hormone-dependent breast cancer. The clinical availability of aminoglutethimide as an inhibitor of cytochrome P-450-mediated steroid hydroxylations prompted study of the precise pharmacological and biochemical effects of this drug. Pharmacokinetic studies revealed that aminoglutethimide alters its own metabolic clearance rate as well as that of dexamethasone, a synthetic glucocorticoid. The metabolic clearance rates of other steroids such as hydrocortisone, medroxyprogesterone acetate, and androstenedione, and estrone are not altered by aminoglutethimide. These findings led to development of a practical regimen of escalating aminoglutethimide dosage in combination with hydrocortisone for treatment of patients with breast carcinoma. Further studies focused upon the biochemical mechanism of estrogen suppression with aminoglutethimide. In vivo, isotopic kinetic data demonstrated that aminoglutethimide inhibits peripheral aromatase by 95 to 98% in postmenopausal women. In vitro experiments indicated that aminoglutethimide can effectively block aromatase directly in human breast tumors as well. With respect to relative potency, aminoglutethimide is a 10-fold more potent aromatase inhibitor than is testololactone but is less potent than are 4-hydroxyandrostenedione and several brominated androstenedione derivatives. Taken together, these studies suggest that aminoglutethimide blocks estrogen production at three sites in women with breast carcinoma: the adrenal cortex, extraglandular peripheral tissues containing aromatase, and breast carcinoma tissue itself.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Santen RJ,Santner SJ,Tilsen-Mallett N,Rosen HR,Samojlik E,Veldhuis JDsubject
Has Abstractpub_date
1982-08-01 00:00:00pages
3353s-3359sissue
8 Suppleissn
0008-5472issn
1538-7445journal_volume
42pub_type
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