Tamoxifen pharmacological effects

The women were randomized to receive either tamoxifen (6681) or placebo (6707) for 5 years. However, the trial was stopped prematurely because the findings provided strong evidence of a reduction in breast cancer with tamoxifen therapy. The results have been released and made available at http //cancertrials.nci.nih.gov. These are the first available data supporting the hypothesis that breast cancer can be pharmacologically prevented in an at-risk female population. The administration of tamoxifen was effective in reducing by 69% the annual rate of ER(+) tumors, both invasive and in situ, but was ineffective in reducing the occurrence of ER(-) neoplasias (Young 1999). 

Conditional KI on adulthood (inactive drug-binding site) Complete KO in all tissues Most relevant model to mimic pharmacological effects in adults Potential incomplete KO Limitation in obtaining KO in brain Potential confounding effects of tamoxifen... 

Issues of the incidence of endometrial cancer during toremifene therapy are controversial. Toremifene can support the growth of tamoxifen-stimulated endometrial cancers in athymic mice [228], so it would not be unreasonable to predict a modest rise in endometrial cancer in patients treated long-term with adjuvant toremifene. The general pharmacology of toremifene in the uterus is the same as that of tamoxifen [288]. However, an analysis of side-effects in adjuvant studies shows no increases in endometrial cancer with toremifene [289]. 

Storniolo, A.M., Nikoloff, D.M., Wu, L., Hillman, G., Hayes, D.F., Stearns, V. and Flockhart, D.A. (2006) Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism implication for optimization of breast cancer treatment. Clinical Pharmacology and Therapeutics, 80, 61-74. 

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]. 

TOREMIFENE Toremifene (fareston) is a triphenylethylene derivative of tamoxifen and has a similar pharmacological profile. Toremifene is indicated for the treatment of breast cancer in women with tumors that are ER-positive or of unknown receptor status. Toremifene has 40 times lower estrogen agonist effect than tamoxifen in vitro, which may make toremifene more effective in combination with an aromatase inhibitor than tamoxifen. 

Toremifene is structurally and pharmacologically related to tamoxifen. It differs structurally from tamoxifen because of halogenation (chlorination) of the ethyl side chain, which reduces its antiestrogenic potency (Fig. 46.20). Toremifene demonstrates beneficial effects on the bone and cardiovascular system and increases HDL levels (142). 

Conditional KO in adulthood More relevant to pharmacological inhibition in adults Flexibility in timing of the KO Potential incomplete KO Limitations in obtaining KO in brain Potential confonnding effects of tamoxifen if nsed Potential scaffolding effects... 

Tamoxifen is the most widely used anti-oestrogen for the treatment of hormone-dependent breast cancer. The specific drug is used as a hormonal therapy for patients who exhibit ER+ breast cancer. The pharmacological activity of tamoxifen depends on its conversion to its active metabolite, endoxifen, by CYP2D6. Mechanisms of action and side effects have been recently revised [34 ]. 

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