Tamoxifen second-generation effects

Second Generation Second generation SERMs were developed with the objective of obtaining ER-targeted pharmaceuticals that lacked the utero-trophic and carcinogenic effects of tamoxifen. The most well characterized second generation SERM is... 

First we shall describe the effects of tamoxifen, a first-generation SERM used as adjuvant treatment in women with breast cancer, on uterine leiomyomas and endometriosis. Considerable space will be devoted to raloxifene, a second-generation SERM administered for the prevention and treatment of postmenopausal women recently tested for the treatment of these two sex-hormone-related diseases. Unfortunately, at present no or very little data are available on the new third-generation SERMs such as lasofoxifene, idroxifene, droloxifene, ospemifene, azomifene, fulvestrant, and MDL 103.323. 

Resistance to tamoxifen is a complex phenomenon and there is evidence that relapse under tamoxifen therapy is linked to the estrogenicity of the drug. Both, the great success of tamoxifen and its liabilities have boosted the search for new analogues in the past 25 years with the goal of identifying a compoimd with increased anti-tumour activity and with reduced side effects. A second generation of structurally related triphenyl-ethylenes like... 

Figure 30 summarizes the characteristic effects of l7(i-estradiol and of the three classes of antiestrogens so far available, namely tamoxifen (first-generation SERM), raloxifene (second-generation SERM) and EM-652 (pure SERM), on the best known parameters of women s... 

First reported in the 1970s, tamoxifen was the first synthetic NR small molecule to show differential tissue effects. The primary reason it has not been widely used to treat menopausal symptoms is the fact that this molecule shows stimulatory effects on the uterus, which cause a significant risk for endometrial cancer [86]. However, tamoxifen remains a first-line treatment for ER-positive breast cancer. A second generation SERM, raloxifene, was originally developed as a tamoxifen follow-up for breast cancer, but it was demonstrated that this molecule has significant osteoporosis protective effects without the endometrial activities relative to tamoxifen [87]. The molecular basis for these ER-modulating activities has been the focal point for a wide body of pharmacological research [88], One proposed mechanism is the differential effects of SERM-bound ER to promote corepressor association versus coactivator association [89, 90]. 

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