Additional SERMs

In addition to the molecules included in Table 1, research in the field of ER modulators has given rise to other novel scaffolds, which may produce additional SERMs to address unmet medical needs in the not-so-distant future.3... 

Additional SERMs are presently undergoing clinical evaluation for treatment of osteoporosis and menopause-related vaginal atrophy (see Chapter 35). 

Recently, leaders in the pharmaceutical industry have developed a list of desired properties for a fourth generation of SERMs (Table 2). In general, future SERMs must oppose endogenous hormone action in the breast and reproductive system while displaying full estrogenic effects in the cardiovasculature, bone and central nervous systems. Additional criteria are that fourth generation compounds possess superior bioavailability compared with existing SERMs and have... 

In addition to those described above, some of the newest compounds emerging in SERM development are ER 3-selective ligands and pathway-selective modulators that target the interaction of the ERs with the transcription factor NFkB. While such compounds are in the early stages of clinical evaluation, thus far they demonstrate great potential for use in the treatment of inflammatory disorders such as arthritis, inflammatory bowel disease, and like other SERMs, cancer [4]. 

Tamoxifen can be used in both premenopausal and postmenopausal women with metastatic breast cancer who have tumors that are hormone-receptor-positive. The toxicities of tamoxifen are described in the section on adjuvant endocrine therapy. The only additional toxicity that one might expect to find in the setting of metastatic breast cancer (specifically bone metastases) is a tumor flare or hypercalcemia, which occurs in approximately 5% of patients following the initiation of any SERM therapy and is not an indication to discontinue SERM therapy. It is generally accepted that this is a positive indication that the patient will respond to endocrine therapy. 

Trioxifene is an older SERM with low estrogenic properties and a higher affinity for ER than tamoxifen. It has shown an unfavorable safety profile in clinical studies of women with breast cancer (leukopenia in 41% of patients, nausea in 31%) (Witte et al. 1986), which is why, in addition to its response rates being no better than in tamoxifen (Lee et al. 1986), its clinical development has been cancelled. 

In addition to lasofoxifene and arzoxifene, bazedoxifene (TSE-424, WAY-140424) is one of the newer SERMs in advanced Phase III clinical development for the prevention and treatment of postmenopausal osteoporosis. In pre-... 

The use of triphenylethylene SERMs as Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration, which is likely due to the involvement of proteins with the ability to bind these compounds. For instance, toremifene is able to reverse MDR and to sensitize human renal cancer cells to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular a 1-acid glycoprotein (AAG), which may limit its tissue availability (Braybrooke et al. 2000). In agreement with this, Chatterjee and Harris (1990) have shown that tamoxifen and 4-OH-tamoxifen were similarly potent in reversing MDR in Chinese hamster ovary (CHO) cells with acquired resistance to adriamycin. However, the addition of AAG (0.5 to 2 mg/ml, the range found in vivo) to cell cultures decreased the effect of tamoxifen on reversing MDR, and at the highest AAG concentration there was a complete reversal of the effects of... 

Other SERMs are currently under development. Diaz Curiel et al. (1998) have proved that a raloxifene analog, LY117018 HC1, is effective in reducing bone loss in OVX rats. In addition, the administration of the substance permits a significant reduction in the minimal effective dose of human parathyroid hormone (PTHh) required in the treatment of osteopenic rats (Hodsman et al. 1999a,b). Two more compounds, FC1271a 41 and HMR-3339 (Ammann et al. 2004), show promising results in preclinical studies. 

Additionally, attention has been focused on some factors that, operating in the hemostatic balance, have been attributed the role of risk markers of clinical events. Thus, increased plasma concentration of factor VII, fibrinogen, plasminogen activator inhibitor type 1 (PAI-1), and the already mentioned Lp(a) have been associated with the occurrence of CHD. Much work has been done on the modulation of these factors by HT (for a review see Cano and Van Baal 2001), and both similarities and differences have been found in the sparse literature on SERM action. Raloxifene and droloxifene decrease fibrinogen more actively than does HT (Walsh et al. 1998 Herrington et al. 2000). In contrast, the effective reduction demonstrated for PAI-1 with oral HT was not confirmed for raloxifene or droloxifene (Walsh et al. 1998 de Valk-de Roo et al. 1999 Herrington et al. 2000). 

This is a proposal to help the clinician to counsel individual women. This process of individualization is crucial and is the best guarantee of a wise use of the different alternatives presently available for an efficient management of the postmenopausal period. Guidelines are only indications of the best choice for a majority of women, but, as health agents of our patients, we have the responsibility of determining how suitable they are for a given woman and introduce the appropriate corrections. In this context SERMs are an early alternative for osteoporosis prevention and treatment that provide an additive protective effect on the breast and are neutral on cardiovascular risk. 

Raloxifene, a more complete uterine antagonist than tamoxifen or clomiphene, significantly reduces leiomyoma size in post-menopausal women [31], yet it is less efficacious at reducing tumor volume in pre-menopausal women [32], This result has been attributed to the poor pharmacokinetic properties of this compound in which extensive conjugative metabolism of the phenol(s) limits the circulating levels of the parent drug. In addition, clinical outcomes in premenopausal women treated with raloxifene suggest that this compound, like tamoxifen and clomiphene, can affect the ovaries via the HPO axis [33]. These data, taken collectively, indicate that current SERMs lack the efficacy, pharmacokinetic, and ovarian safety properties needed to treat leiomyoma in ovulatory women. 

TAS-108 (SR16234) is a novel and orally active steroidal compound with a proposed additional molecular mode-of-action that is different from that of SERMs such as tamoxifen and raloxifene [157]. TAS-108 is a full estrogen receptor-a antagonist, and it should also recruit co-activator transcriptional intermediary factor 2 to ER-j6, which may have a preventive effect on bone loss [157]. 

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