Raloxifene is a Tissue‐Selective Agonist/Antagonist That Functions through the Estrogen Receptor

Fuchs-Young, Robin; Glasebrook, A. L.; Short, Lorri L.; Draper, Michael W.; Rippy, Marian K.; Cole, Harlan W.; Magee, David E.; Termine, John D.; Bryant, Henry U.

doi:10.1111/j.1749-6632.1995.tb31392.x

Cited by 75 publications

(38 citation statements)

References 2 publications

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“…For example, tamoxifen and toremifene, the SERMs for which the longest clinical experience is available, act as estrogen antagonists in breast tissue and as estrogen agonists in bone and endometrium (Hayes et al 1995, Tomas et al 1995. On the other hand, raloxifene, an agent currently used to prevent osteoporosis, behaves as an estrogen antagonist in both breast and endometrium (Black et al 1983, Fuchs-Young et al 1995. These differences in the activity of SERMs appear to be related to differences in their molecular structures (e.g.…”

Section: The Role Of Er Blockers In Breast Cancermentioning

confidence: 99%

Chemoprevention of breast cancer and the trials of the National Surgical Adjuvant Breast and Bowel Project and others.

Smith

Good²

2003

Endocrine-Related Cancer

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The idea of breast cancer prevention by hormonal means stemmed from the results of treatment trials, many of them carried out by the National Surgical Adjuvant Breast and Bowel Project (NSABP). Over the years, a number of NSABP treatment studies demonstrated that breast cancer recurrence was reduced in women with the disease who were given tamoxifen, a selective estrogen receptor (ER) modulator (SERM). Five subsequent tamoxifen prevention trials with this agent have shown a 48% reduction in ER-positive cancers, but no effect for ER-negative cancers, and an increase in endometrial cancer and thromboembolic events. The drug raloxifene, another SERM, originally examined as an osteoporosis agent, has also shown promise for the prevention of breast cancer, although, as with tamoxifen, the drug carries a risk for thromboembolic events. There is recent evidence in a large treatment trial that the aromastase inhibitor anastrazole, a 'pure anti-estrogen', holds promise as a breast cancer preventive agent. Longer follow-up and the testing of additional agents is required before these drugs can be used widely for prevention. In addition, future research should focus on the identification of at-risk women who can perhaps be targeted for specific prevention agents.

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Section: The Role Of Er Blockers In Breast Cancermentioning

confidence: 99%

Chemoprevention of breast cancer and the trials of the National Surgical Adjuvant Breast and Bowel Project and others.

Smith

Good²

2003

Endocrine-Related Cancer

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“…Raloxifene (LY 139481) is an ER ligand that belongs to a class of compounds called selective estrogen receptor modulators (SERMs) [16,17]. Raloxifene is a benzothiophene derivative that binds to the ER with nanomolar affinity and has tissue-selective agonist and antagonist properties.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of estrogen-stimulated growth of uterine leiomyomas by selective estrogen receptor modulators

et al. 1996

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Uterine leiomyoma is the most frequent gynecologic neoplasm in women. By using a panel of cell lines derived from spontaneous Eker rat leiomyomas, we examined the estrogen-responsive phenotype of these tumor cells. Leiomyoma-derived ELT cell lines proliferated in response to estrogen, and estrogen-induced cell proliferation could be inhibited by the estrogen antagonist ICI 182780 and the selective estrogen-receptor modulators (SERMs) raloxifene and tamoxifen. In addition to inhibiting cell growth, these antagonists also inhibited estrogen-induced increases in progesterone-receptor expression. These data indicate that SERMs such as raloxifene and tamoxifen act as estrogen antagonists in uterine myometrial cells and suggest that this class of compounds may be effective for treatment of this important gynecologic neoplasm.

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“…Raloxifene (previously called keoxifene) is a benzothiophene derivative that binds to the estrogen receptor with high affinity. 32 Raloxifene has tissue specificity, with estrogen antagonistic effects on the breast and uterus but with estrogen agonist effects on bone and plasma cholesterol concentrations. 33,34 Raloxifene prevents bone loss without producing uterine proliferation.…”

mentioning

confidence: 99%

Randomized, Double-Blind, Placebo-Controlled Study on Effects of Raloxifene and Hormone Replacement Therapy on Plasma NO Concentrations, Endothelin-1 Levels, and Endothelium-Dependent Vasodilation in Postmenopausal Women

Saitta

Altavilla

Cucinotta

et al. 2001

ATVB

166

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Abstract-The endothelium is thought to play an important role in the genesis of atherosclerosis, and several lines of evidence suggest that the effect of an intervention on endothelial function might predict its involvement in coronary disease progression and in the rate of cardiovascular events. Estrogen has direct effects on the blood vessel wall, indicating that vascular endothelium may play a key role in the cardiovascular protective effects of hormone replacement therapy (HRT). Raloxifene relaxes coronary arteries in vitro by an estrogen receptor-dependent and NO-dependent mechanism, thus suggesting that this selective estrogen receptor modulator could also have beneficial effects on endothelial function. This study compared the effects of HRT and raloxifene on NO products, endothelin-1 plasma levels, and endothelium-dependent vasodilatation in postmenopausal women. Healthy postmenopausal women (nϭ90) were enrolled in a double-blind, randomized, placebocontrolled, 6-month trial. Women were randomly assigned to receive continuous HRT (1 mg 17␤-estradiol combined with 0.5 mg norethisterone acetate), raloxifene (60 mg/d), or placebo for 6 months. Flow-mediated endothelium-dependent vasodilation of the brachial artery, plasma NO concentrations, and endothelin levels were measured at baseline and after 6 months of therapy. The mean baseline level of NO breakdown products was 26.5Ϯ10.7 mol/L and increased to 36.3Ϯ11.4 mol/L after 6 months of treatment with raloxifene. The mean baseline plasma endothelin level was 17.3Ϯ8.9 pg/mL and decreased to 11.5Ϯ2.1 pg/mL after 6 months of treatment with the selective estrogen receptor modulator. The mean baseline ratio of NO (breakdown products) to endothelin was also significantly increased at the end of treatment with raloxifene. Postmenopausal women treated with HRT had similar changes in plasma nitrites/nitrates and endothelin levels as well as in the ratio of NO to endothelin. In contrast, these markers of endothelial function did not change in the placebo-treated women. Flow-mediated endothelium-dependent vasodilation of the brachial artery was 8.3Ϯ2.1% at baseline and increased to 12.3Ϯ2.1% after 6 months of treatment with raloxifene. HRT also caused a significant and similar increase in flow-mediated endothelium-dependent vasodilation. No change in flow-mediated vasodilation was observed in the participants treated with placebo. We conclude that raloxifene therapy and HRT influence endothelial function and improve flow-mediated endothelium-dependent vasodilation to a comparable extent in healthy postmenopausal women at least after a 6-month treatment period. However, further investigation is warranted to enhance our understanding of the mechanisms of the effect of raloxifene on vascular function and to determine whether its effect on endothelial function may contribute to the reduction in cardiovascular-related morbidity and mortality. Key Words: raloxifene Ⅲ hormone replacement therapy Ⅲ nitric oxide Ⅲ endothelin-1 Ⅲ endothelium P opulation-based observational studi...

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Raloxifene is a Tissue‐Selective Agonist/Antagonist That Functions through the Estrogen Receptor

Cited by 75 publications

References 2 publications

Chemoprevention of breast cancer and the trials of the National Surgical Adjuvant Breast and Bowel Project and others.

Chemoprevention of breast cancer and the trials of the National Surgical Adjuvant Breast and Bowel Project and others.

Inhibition of estrogen-stimulated growth of uterine leiomyomas by selective estrogen receptor modulators

Randomized, Double-Blind, Placebo-Controlled Study on Effects of Raloxifene and Hormone Replacement Therapy on Plasma NO Concentrations, Endothelin-1 Levels, and Endothelium-Dependent Vasodilation in Postmenopausal Women

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