Aromatase inhibitors for treatment of XXXX : current concepts and new perspectives.

@entity172 @entity1 @entity19517 @entity0 @entity35 @entity440 @entity5 @entity6239 @entity53 @entity19836 @entity18056 @entity1815 @entity7044 @entity2671 @entity165
@entity172 provide the major hormonal support for endocrine-dependent @entity1 mammary @entity5 . In postmenopausal @entity1 , the extraglandular aromatization of the adrenal prehormone, @entity2671 to @entity1815 is the major pathway for @entity172 biosynthesis. @entity1815 can then be converted into @entity53 or into an inactive conjugate, @entity19517 . Recent data suggest that the @entity172 may also be synthesized in situ by @entity1 @entity0 , either from @entity2671 via aromatase, or from @entity19517 via the enzyme, @entity18056 . Our enzyme kinetic studies support the predominance of the @entity18056 pathway for in situ @entity172 biosynthesis. The ability of @entity19517 to stimulate colony formation of the @entity7044 -induced @entity35 mammary @entity5 in the clonogenic assay, suggests that this in situ pathway has biologic relevance. Aromatase inhibitors can be used to suppress the levels of circulating @entity1815 , @entity19517 , and @entity53 in postmenopausal @entity1 . @entity6239 , the major inhibitor currently used clinically, acts in a competitive fashion and blocks @entity165 side chain cleavage and 11 beta-hydroxylase as well as aromatase. Clinical studies indicate that the combination of @entity6239 plus replacement glucocorticoid causes @entity0 regression with the same frequency and for the same duration as surgical ablative therapies such as adrenalectomy or hypophysectomy. @entity6239 also induces a similar rate of @entity5 regression as achieved with the antiestrogen, @entity440 . However, because @entity440 is associated with fewer side effects, this antiestrogen is to be preferred over use of @entity6239 as first-line hormonal treatment for @entity1 with @entity0 . Several specific suicide inhibitors of @entity6239 such as @entity19836 are being developed and have proven effective in early clinical trials with @entity0 @entity1 . Further development of active aromatase inhibitors should allow precise control of @entity53 levels in @entity1 with @entity0 . This ability to perform an ' @entity172 clamp' may allow new strategies to be developed in which hormone depletion followed by repletion can produce a synchronization of @entity5 cell DNA synthesis. If achievable, such manipulations may allow potentiation of the effects of cytotoxic chemotherapy. This latter concept is currently being rigorously tested in basic and in clinical investigative studies.
