Evista
Structure-function relationships of the raloxifene-estrogen receptor-alpha complex for regulating transforming growth factor-alpha expression in breast cancer cells.

Liu H, Park WC, Bentrem DJ, McKian KP, Reyes Ade L, Loweth JA, Schafer JM, Zapf JW, Jordan VC.

Robert H. Lurie Comprehensive Cancer Center and the Department of Surgery, Northwestern University Medical School, Chicago, Illinois 60611, USA.

Amino acid Asp-351 in the ligand binding domain of estrogen receptor alpha (ERalpha) plays an important role in regulating the estrogen-like activity of selective estrogen receptor modulator-ERalpha complexes. 4-Hydroxytamoxifen is a full agonist at a transforming growth factor alpha target gene in situ in MDA-MB-231 human breast cancer cells stably transfected with the wild-type ERalpha. In contrast, raloxifene (Ral), which is also a selective estrogen receptor modulator, is a complete antiestrogen in this system. Because D351G ERalpha allosterically silences activation function-1 activity in the 4-hydroxytamoxifen-ERalpha complex with the complete loss of estrogen-like activity, we examined the converse interaction of amino acid 351 and the piperidine ring of the antiestrogen side chain of raloxifene to enhance estrogen-like action. MDA-MB-231 cells were either transiently or stably transfected with Asp-351 (the wild type), D351E, D351Y, or D351F ERalpha expression vectors. Profound differences in the agonist and antagonist actions of Ralcenter dotERalpha complexes were noted only in stable transfectants. The agonist activity of the Ralcenter dotERalpha complex was enhanced with D351E and D351Y ERalpha, but raloxifene lost its agonist activity with D351F ERalpha. The distance between the piperidine nitrogen of raloxifene and the negative charge of amino acid 351 was critical for estrogen-like actions. The role of the piperidine ring in neutralizing Asp-351 was addressed using compound R1h, a raloxifene derivative replacing the nitrogen on its piperidine ring with a carbon to form cyclohexane. The derivative was a potent agonist with wild type ERalpha. These results support the concept that the side chain of raloxifene shields and neutralizes the Asp-351 to produce an antiestrogenic ERalpha complex. Alteration of either the side chain or its relationship with the negative charge at amino acid 351 controls the estrogen-like action at activating function 2b of the selective estrogen receptor modulator ERalpha complex.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11751902&dopt=Abstract raloxifene Evista



Evista
Cost-effectiveness of raloxifene and hormone replacement therapy in postmenopausal women: impact of breast cancer risk.

Armstrong K, Chen TM, Albert D, Randall TC, Schwartz JS.

Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6021, USA. karmstro mail.med.upenn.edu

OBJECTIVE: To examine the life expectancy and cost-effectiveness of hormone replacement therapy (HRT) and raloxifene therapy in healthy 50-year-old postmenopausal women. METHODS: We performed a cost-effectiveness analysis using a Markov model, discounting the value of future costs and benefits to account for their time of occurrence. RESULTS: Both HRT and raloxifene therapy increase life expectancy and are cost-effective relative to no therapy for 50-year-old postmenopausal women. For women at average breast cancer and coronary heart disease risk, lifetime HRT increases quality-adjusted life expectancy more (1.75 versus 1.32 quality-adjusted life years) and costs less ($3802 versus $12,968) than lifetime raloxifene therapy. However, raloxifene is more cost-effective than HRT for women at average coronary risk who have a lifetime breast cancer risk of 15% or higher or who receive 10 years or less of postmenopausal therapy. Raloxifene is also the more cost-effective alternative if HRT reduces coronary heart disease risk by less than 20%. CONCLUSIONS: Assuming the benefit of HRT in coronary heart disease prevention from observational studies, long-term HRT is the most cost-effective alternative for women at average breast cancer and coronary heart disease risk seeking to extend their quality-adjusted life expectancy after menopause. However, raloxifene is the more cost-effective alternative for women at average coronary risk with one or more major breast cancer risk factors (first-degree relative, prior breast biopsy, atypical hyperplasia or BRCA1/2 mutation). These results can help inform decisions about postmenopausal therapy until the results of large scale randomized trials of these therapies become available.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11755544&dopt=Abstract raloxifene Evista



Evista
Estrogen alone or combined with medroxyprogesterone but not raloxifene reduce myocardial infarct size.

Sbarouni E, Iliodromitis EK, Bofilis E, Kyriakides ZS, Kremastinos DT.

2nd Department of Cardiology, Onassis Cardiac Surgery Center, 356 Syngrou Avenue, 176 74 Athens, Greece. elbee ath.forthnet.gr

We investigated whether estrogen protects the ischemic myocardium in oophorectomized female rabbits fed with a cholesterol-enriched diet, whether the addition of a progestin compound attenuates the beneficial effect of estrogen and whether raloxifene also limits myocardial necrosis. We treated 32 female oophorectomized hypercholesterolemic rabbits with (a) placebo (N=8, group I), (b) conjugated estrogens alone (N=8, group II), (c) conjugated estrogens combined continuously with medroxyprogesterone acetate (N=8, group III) and (d) raloxifene (N=8, group IV) all for 4 weeks. All rabbits underwent 30 min of ischemia and 120 min of reperfusion. Both infarct size (0.38+/-0.08 and 0.45+/-0.05 in groups II and III, respectively, vs. 0.78+/-0.07 in group I, P<0.005) and infarct size/risk zone% (26.34+/-4.18 and 35.01+/-4.39 in groups II and III, respectively, vs. 52.18+/-7.84 in group I, P<0.05) were significantly smaller in the estrogen treatment groups compared to placebo. No significant difference was observed between groups II and III. There was no significant difference between groups I and IV for infarct size (0.78+/-0.07 vs. 0.69+/-0.08, respectively) or for infarct size/risk zone% (52.18+/-7.84 vs. 47.17+/-4.3). Short-term estrogen protects ischemic myocardium in hypercholesterolemic oophorectomized female rabbits; this effect is not attenuated by the addition of a progestin compound. Raloxifene, however, does not decrease infarct size compared to placebo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12706470&dopt=Abstract raloxifene Evista



Evista
Raloxifene enhances nitric oxide release in rat aorta via increasing endothelial nitric oxide mRNA expression.

Rahimian R, Dube GP, Toma W, Dos Santos N, McManus BM, van Breemen C.

The Vancouver Vascular Biology Research Center, University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada.

We report the modulatory effects of chronic oral LY139481 (raloxifene) on basal release of nitric oxide (NO) and mRNA levels of endothelial NO synthase (eNOS) in rat thoracic aorta. Constrictor dose-response curves to phenylephrine were generated before and after pretreatment with N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase. Aortic segments were obtained from four groups of rats gavaged orally for 21 days: (i) ovariectomized, (ii) sham, (iii) ovariectomized estradiol-treated, and (iv) ovariectomized raloxifene-treated. Intact aortic rings from sham rats and ovariectomized rats receiving raloxifene and estrogen showed a greater potentiation of the phenylephrine responses after L-NAME. Semi-quantitative reverse transcription-polymerase chain reaction indicated a gender-based difference in eNOS mRNA expression in thoracic aorta. Moreover, we demonstrated that eNOS mRNA expression in the upper thoracic aorta was significantly higher in treatment groups. These results show that chronically administered raloxifene is exerting a potentially important vasculo-protective effect by stimulating eNOS expression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11779577&dopt=Abstract raloxifene Evista



Evista
The MORE trial: multiple outcomes for raloxifene evaluation--breast cancer as a secondary end point: implications for prevention.

Dickler MN, Norton L.

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

Breast cancer is a common disease in the United States and Europe and is therefore a major target for prevention strategies. Estrogen plays a central role in its pathogenesis, and treatment with estrogen deprivation has long been recognized to be an effective therapy. Tamoxifen is the first selective estrogen receptor modulator (SERM) to be widely used for the treatment of breast cancer and has been demonstrated to reduce the risk of breast cancer in high-risk women. Raloxifene is a second-generation SERM that has estrogenic effects on bone and lipid metabolism, and antiestrogenic effects on breast tissue. Unlike tamoxifen, raloxifene displays antiestrogenic effects on the endometrium and may serve as a safer alternative to tamoxifen in the prevention setting. The MORE trial is a multicenter randomized placebo-controlled trial designed to determine whether 3 years of raloxifene reduces the risk of fracture in postmenopausal women with osteoporosis. As a secondary end point of the trial, raloxifene was shown to reduce the risk of both in situ and invasive breast cancer by 65% (RR = 0.35; 95% CI = 0.21-0.58; P < 0.001). The benefits were most significant in women who developed estrogen receptor (ER)-positive cancers, with a relative risk of 0.10 (95% CI = 0.04-0.24). This reduced incidence of breast cancer may be due to an anticarcinogenic effect or to a slowing of growth of occult ER-positive cancer, with a shift to the right in the time-to-cancer curve. A second large-scale prevention trial in breast cancer comparing tamoxifen to raloxifene is presently enrolling cancer-free, but high-risk postmenopausal women (the STAR trial). Future directions include combined estrogen blockade of the breast by the addition of an aromatase inhibitor to a SERM. New trial designs, including those based on biochemical changes at the tissue level, will be required to allow future progress in this field with adequate rapidity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11795345&dopt=Abstract raloxifene Evista



Evista
[Amelioration of ischemia- and reperfusion-induced myocardial injury by the selective estrogen receptor modulator, raloxifene, in the canine heart]

[Article in Japanese]

Ogita H, Node K, Asanuma H, Sanada S, Takashima S, Asakura M, Kitakaze M, Hori M.

Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Yamada-oak 2-2, Suita, Osaka 565-0871.

BACKGROUND: 17 beta-estradiol reduces myocardial infarct size which is mediated by nitric oxide (NO) and the opening of Ca (2+)-activated K+ (KCa) channels. Raloxifene, a selective estrogen receptor modulator, demonstrates acute coronary artery vasorelaxing effects. Whether raloxifene reduces ischemia/reperfusion injury and what mechanisms are involved in the cardioprotective effects were investigated. METHODS: Infarct size was measured in open-chest dogs following occlusion of the left anterior descending coronary artery for 90 min and subsequent reperfusion for 6 hr. The incidence of ventricular fibrillations during reperfusion period was also observed. Infusion of raloxifene and/or other drugs into the left anterior descending coronary artery was initiated 10 min before coronary occlusion and continued until 1 hr after reperfusion started without an occlusion period. RESULTS: Infarct size was reduced in the raloxifene (5 micrograms/kg/min) group compared with the control group (6.8 +/- 4.2% vs 40.9 +/- 3.9% of the area at risk, p < 0.01). Either NG-nitro-L-arginine methyl ester, the inhibitor of NO synthase (infarct size: 22.8 +/- 5.4%, p < 0.05 vs raloxifene or the control) or charbdotoxin, the blocker of KCa channels (infarct size: 23.5 +/- 5.1%, p < 0.05 vs raloxifene or the control), partially attenuated the infarct size-limiting effect, and combination of both agents completely abolished the effect (infarct size: 37.7 +/- 5.8%). The incidence of ventricular fibrillations was also less in the raloxifene group than in the control group(11% vs 44%, p < 0.05). CONCLUSIONS: Raloxifene reduces myocardial infarct size and the incidence of ventricular fibrillations by NO- and the opening of KCa channels-dependent mechanisms in canine hearts.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11828800&dopt=Abstract raloxifene Evista