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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
A number of other triphenylethylene analogues have been studied through the years but have not reached the approval stage as oncology agents, although two (ospemifene and clomifene) have been approved for noncancer estrogen-related disorders. Other analogues include idoxifene and droloxifene (Figure 8.7). Structures of the other well-known triphenylethylene analogues idoxifene, droloxifene, ospemifene, and clomifene.
Hormones as Immune Modulating Agents
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Estrogen and androgen receptors are present in the thymus and in the bursa of Fabricius; however, classical estrogen receptors (detectable by the dextran-coated charcoal assay) in secondary lymphoid tissue are not present, with the exception of CD8+ T lymphocytes, which express receptors for estradiol. Progesterone is capable of acting through GC receptors, although the existence of specific receptors for this hormone in lymphoid cells has also been described. At high concentrations estrogens and androgens also act on GC receptors [26,240–242]. There are indications for the existence of as yet unidentified steroid receptors that affect lymphocyte reactions. For instance, estradiol and triphenylethylene antiestrogens (e.g., tamoxifen or toremifene) both sensitize lymphoid and nonlymphoid target cells for cell-mediated killing in the absence of classical estrogen receptors. This finding suggests the existence of a novel steroid receptor on which both estradiol and antiestrogens act synergistically rather than antagonistically [243]. Membrane-bound steroid receptors which include the polyglycoprotein (PGP) pump have also been described. Triphenylethylene-derived antiestrogens are capable of inhibiting lymphocyte proliferation under conditions in which estradiol has no effect. A membrane-bound antiestrogen binding site for which the natural ligand is unknown seems to be involved in this phenomenon [243].
Histogenesis of Irreversible Changes in the Female Genital Tract After Perinatal Exposure to Hormones and Related Substances
Published in Takao Mori, Hiroshi Nagasawa, Toxicity of Hormones in Perinatal Life, 2020
Triphenylethylene dérivâtes (tamoxifen, clomiphene) and nafoxidine have a varying estrogen agonist-antagonist spectrum in different species and tissues. Clomiphene, tamoxifen, and nafoxidine are estrogen agonists in the mouse uterus and vagina.101,102 When neonatal female mice were treated with daily doses of 5 μg of these drugs for the first 5 days after birth, HCE occurred in the cervicovaginal region at 8 weeks after birth. Tamoxifen, ICI 47.699 (ds-isomer of tamoxifen), and clomiphene were more effective than nafoxidine in inducing HCE, and even more so than estradiol and DES.103 “More effective” means larger areas covered with HCE. With clomiphene and tamoxifen, large areas with HCE were not only seen in the vaginal fornices and CCC, but also in a large region in the upper part of the vagina, which is only rarely involved after treatment with estradiol and DES. Glandlike downgrowths also appeared earlier than with estradiol or DES. These results are similar to those reported by Taguchi and Nishizuka.104
Ospemifene efficacy and safety data in women with vulvovaginal atrophy
Published in Gynecological Endocrinology, 2020
Lino Del Pup, Rafael Sánchez-Borrego
For women with estrogen-therapy contraindication, nonestrogen therapeutic options for VVA include ospemifene and DHEA [12]. Ospemifene is a Selective Estrogen Receptor Modulator (SERM), a triphenylethylene derivative, whose primary mechanism of action is mediated by binding of nuclear estrogen receptors (ER), ERα (0.8%) and ERβ (0.6%) [13,14]. Ospemifene is metabolized by the liver into two major metabolites, 4- hydroxyospemifene (70%) and 4′-hydroxyospemifene (7%) and several minor metabolites. Several CYP enzymes (CYP2C9, CYP2C19, CYP2B6 and CYP3A4) are responsible for the hepatic clearance of ospemifene [14–17]. It is primarily excreted in the bile and eliminated in the feces (75%), although small amounts can be eliminated in the urine (7%) in about 24–26 h [13,17–19]. Following oral administration, ospemifene achieves the maximum concentration at 3–4 h in the fed state and 1–8 h in the fasted state. In fed state the suggested dose range of 60–240 mg, while in fasted state the dose range of 25–200 mg. Hence, the daily recommended dose is 60 mg taken with food [13–19].
Recent advances in computational design of potent aromatase inhibitors: open-eye on endocrine-resistant breast cancers
Published in Expert Opinion on Drug Discovery, 2019
Angelo Spinello, Ida Ritacco, Alessandra Magistrato
Building on these burgeoning results, a structure-based approach was used to design NOR analogues, which displayed a high ERα and AI inhibitory activity. In particular, 4ʹ-hydroxynorendoxifen (Figure 5) exhibited a raised inhibitory activity with respect to its parent compound NOR [117]. A series of triphenylethylene bisphenol analogues was designed by removing the aminoethoxy chain of NOR, eliminating in this manner the possibility of E/Z isomerization [118]. Moreover, the replacement of the ethyl group with an imidazole ring resulted in an optimal HA inhibition and ER antagonistic affinity (Compound D1, Figure 5), as also proved by ER transcriptional assays in ER+ MCF-7 BC cell lines. Finally, the same group designed aminated NOR derivatives bearing amino groups or nitro moieties, while eliminating the two aminoethyl tails [119]. The most potent dianiline compound (Compound D2, Figure 5) resulted to be a potent inhibitor, although less than the previous dual compounds. Computational studies on these compounds were so far limited to docking studies, revealing that these drugs occupy the binding pocket of HA and ERα.
Beyond estrogen: advances in tissue selective estrogen complexes and selective estrogen receptor modulators
Published in Climacteric, 2019
Tamoxifen, a triphenylethylene, is an antagonist in the breast competing against the formation of normal interactions between 17β-estradiol and its receptor complex, leading to an antiproliferative effect in breast cancer cells. If no transcription occurs, there is a lack of cell growth or arrest with apoptosis. However, the tamoxifen receptor complex is an agonist in the lung, liver, bone, and uterus. A meta-analysis of large prospective trials of tamoxifen for prevention showed that the breast cancer rate decreased by 38% overall, with a 48% reduction for ER-positive breast cancers10. In an updated follow-up of the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (NSABP) in women at risk for breast cancer, Vogel et al.11 reported that 5–8 years of tamoxifen significantly reduced the incidence of invasive breast cancer, with a persistence of 7–12 years. When given as an adjuvant for ER-positive cancers for 2–5 years, tamoxifen reduced the risk of contralateral breast cancer in women for both invasive breast cancer and ductal carcinoma in situ up to 15 years of follow-up. Ten years of tamoxifen is recommended due to a stronger reduction in recurrent breast cancer compared to 5 years of use, with 3.7% fewer recurrences and an absolute mortality reduction of 2.8% in a large trial of 7000 women12. Tamoxifen is the medication of choice for premenopausal women at increased breast cancer risk13.