Pure antiestrogens

Originally, the inspiration to substitute E2 at the 7a-position came from the observation that ER could be purified on resin columns derivatized with E2 through 

Fulvestrant has been compared to tamoxifen for the treatment of advanced breast cancer in postmenopausal women. In a study of587 patients, there was no significant difference between fulvestrant and tamoxifen at a median follow-up of 14.5 months for the primary endpoint of time to progression (median 6.8 versus 8.3 months, respectively) however, the tamoxifen group showed slightly better results. Hence, fulvestrant displayed similar efficacy to tamoxifen and was well tolerated [392]. 

Although fulvestrant has not proven to be better than other therapies, it clearly represents an additional treatment option for women with breast cancer whose disease fails to respond to other therapies. Currently, its use as a third-line therapy results in a 28% rate of stable disease with a partial response in this group of patients. In addition, its high tolerability profile and novel mode of action offer the potential for 

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ER antagonists comprise two broad categories pure antiestrogens and SERMs. A summary of the different biological functions associated with some of the known antiestrogens is displayed in Table 1. 

Wakeling AE (1993) The future of new pure antiestrogens in clinical breast cancer. Breast Cancer Res Treat 25 1... 

Labrie F, Labrie C, Belanger A, Simard J, Gauthier S, Luu-The V, et al. (1999) EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and the endometrium. J Steroid Biochem Mol Biol 69 51-84... 

Donath J, Nishino Y (1998) Effect of partial versus pure antiestrogens on ovulation and the pituitary-ovarian axis in the rat. J Steroid Biochem Mol Biol 66 247-254... 

Type II antiestrogens, pure antiestrogens, or selective estrogen receptor down-regulators (SERDs) (Howell et al. 2004b) have no estrogen-like properties in laboratory assays. 

The pure antiestrogens were discovered about 20 years ago by Wakeling and collaborators (Wakeling and Bowler 1987). To date, a few distinct compounds... 

The aim of the present review is to update the recent discoveries on the mechanisms of action, biological effects, clinical trials, and potential clinical utility of pure antiestrogens. 

The main compounds that have demonstrated a pure antiestrogenic activity in the laboratory are the following (Fig. 6.1) ... 

ICI 164384. This is the first pure antiestrogen discovered (Wakeling and Bowler 1987). This compound is a 7o -alkylamine derivative of 17/i-estradiol, with a 16-atom carbon chain in the la position. 

Other compounds, such as ZK-703 and ZK-253, are currently under preclinical testing, and preliminary data show a pure antiestrogen activity in xenograft breast cancer models (Hoffmann et al. 2004). 

Pure antiestrogens are distinguishable form other SERMs in terms of their mechanism of action, although both classes of agent mediate their effects through the two types of estrogen receptors (ERa and ER/J). 

Pure antiestrogens also act as competitive inhibitors of the estradiol-ER complex. For instance, ICI164384 is a competitive antagonist of both ERa and ER/ (Barkhem et al. 1998). In MCF-7 cells, similar amounts of estradiol and RU58668 are bound to ER (Jensen and Khan 2004). 

Pure antiestrogens also exert a unique mechanism of action they decrease intracellular levels of ER (Wakeling 2000). Fulvestrant is able to bind to newly... 

Fig. 6.2. Proposed mechanisms of action of pure antiestrogens (fulvestrant). 1 Fulvestrant (ICI) binds to estrogen receptor (ER). 2 Fulvestrant binding to ER accelerates receptor degradation ( ER down-regulator ). 3 Rate of dimerization and nuclear localization of fulvestrant-ER complex is reduced. 4 Reduced binding of fulvestrant-ER to ERE. 5 No transcription of estrogen-responsive genes since AF-1 and AF-2 are inactive, no coactivators are recruited and the activity of RNA polymerase II is not activated (or inhibited) (Wakeling 2000)...

The majority of the actions of pure antiestrogens have been described in studies designed in cell cultures (effects in vitro) or in experiments performed in animals. During the last few years, only a few clinical studies have been completed. The main objective of the majority of the studies has been to demonstrate the pure antiestrogenic action of these compounds. 

These studies have been focused on the effects of pure antiestrogens on gene expression, on cell growth and proliferation, and on the effects on different growth factors. 

In the initial studies with pure antiestrogens, both ICI 164384 and fulvestrant inhibited cell growth and arrested the cell cycle in the Gi phase. These effects were two orders of magnitude more potent than those achieved with tamoxifen in the same experimental conditions (Wakeling and Bowler 1987). 

To date, all the experiments done in animals with pure antiestrogens have disregarded any estrogenic actions of these compounds. Some of the described effects are presented here, arranged by the tissue or organ where they have been described (Table 6.2). 

The main potential utility of the pure antiestrogens is in the treatment of breast cancer. Several studies on their effects on the breast demonstrate both the pure antiestrogenic action of the tested compounds and their beneficial effects on breast cancer treatment. In experiments conducted in nude mice xenotrans-planted with two different human estradiol-dependent breast tumors, a single injection of fulvestrant provided an antitumor efficacy equivalent to that of daily tamoxifen treatment for at least 4 weeks (Wakeling et al. 1991). Additionally, RU 58668 was able to induce up to 30% disappearance of MCF-7 breast... 

Table 6.2. Effects of pure antiestrogens on experimental animals ...

The effects of pure antiestrogens in the uterus have also been extensively studied, since it is an estrogen-dependent organ and the target of the main side effects of tamoxifen therapy, such as endometrial hyperplasia, hypertrophy of glandular epithelium, or even focal cellular atypia (Sourla et al. 1997). 

The overall uterine effects obtained in animals treated with the different compounds make it possible to assume that pure antiestrogens could be used in the treatment of endometrial disorders and endometrial carcinoma (Gradishar and Jordan 1997). 

By acting on the vessel wall, estradiol significantly inhibited superoxide anion-induced vascular smooth muscle cell proliferation, whereas the pure antiestrogen ICI 164384 reversed the inhibitory effect of estradiol (Cathapermal et al. 1998). Fulvestrant also reversed the estradiol-induced increase in blood flow in rabbit aorta (Hegele-Hartung et al. 1997). 

There is very little information concerning the performance of pure antiestrogens in clinical conditions, and all studies have been done with fulvestrant. 

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