Evista
Selective estrogen receptor (ER) modulators differentially regulate phospholipase D catalytic activity in ER-negative breast cancer cells.

Eisen SF, Brown HA.

Department of Molecular Medicine, Veterinary Medical Center, Field of Pharmacology, Cornell University, Ithaca, New York, USA.

Recent successes in the pharmacotherapeutic treatment of breast cancer are associated with the use of selective estrogen receptor modulators. Two commonly prescribed pharmaceuticals in this class, tamoxifen and raloxifene, have been shown to have effects through estrogen receptor (ER)-independent mechanisms. Hyperactivation of phospholipase D (PLD) in certain tumor-derived cell lines have been reported, and recent findings suggest a role for PLD in transformation and metastasis. In the present study, we compare the effects of tamoxifen and raloxifene on PLD in the ER-positive mammary epithelial cell line MCF-12A, and the ER-negative, highly tumorigenic mammary carcinoma cell line MDA-MB-231. Our data demonstrate that tamoxifen and raloxifene have differential effects on PLD catalytic activity. Tamoxifen stimulates PLD in both ER-positive and -negative cells in vivo, whereas raloxifene inhibits PLD activity in these same cell types. In addition, we show that the active metabolite 4-OH-tamoxifen can be used to pharmacologically discriminate the two isoforms of PLD, through a stimulatory effect on PLD1 and an inhibitory effect on PLD2. Using recombinant PLD1, we show stimulation by tamoxifen requires a factor present in Sf21 insect cells that is not required for inhibition of PLD1 by raloxifene. Furthermore, tamoxifen stimulation and raloxifene inhibition of PLD activities are independent of the amino-terminal portion of PLD1 (amino acids 1-324). Knowledge of the mechanisms of action of these drugs on PLD may provide insights into the pharmacological action of these drugs and the role of PLD in some cancers.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12237338&dopt=Abstract raloxifene Evista



Evista
[What can we expect of raloxifene in the treatment of postmenopausal osteoporosis--views of a gynecologist]

[Article in Czech]

Chmel R, Rob L, Strnad P.

Gynekologicko-porodnicka klinika, UK, 2. LF a FN v Motole, Praha. Chmel.Roman seznam.cz

OBJECTIVE: Evaluation of positive properties and side effects of raloxifene treatment with respect to its potential use as agent to improve women's health and quality of life in postmenopausal years. DESIGN: A review article. SETTING: Obstetrics and Gynaecology Department, Charles University 2nd Medical Faculty and Teaching Hospital Motol, Prague. SUBJECT: Estrogen use may protect against osteoporosis and cardiovascular disease, but may increase the risk of breast cancer in long-term treated women and also may increase the risk of irregular uterine bleeding (in combination with gestagen in non-hysterectomized women) in perimenopause and postmenopause. Drugs with tissue-specific estrogenic effects are termed selective estrogen receptor modulators (SERM). Tamoxifen is the first SERM successfully used in the prevention and treatment of breast cancer. Another SERM raloxifene is widely used in the prevention and treatment of postmenopausal osteoporosis, especially in women without climacteric complaints. Therapy with raloxifene increases bone mineral density, lowers serum concentrations of total and low-density lipoprotein cholesterol, and does not stimulate endometrium and breast. Evaluation of another potential positive effects (reducing size of uterine leiomyomas, etc.) warrants further investigation. CONCLUSION: Raloxifene can be used in postmenopausal women free of climacteric symptoms for the prevention and treatment of postmenopausal osteoporosis with no increased risk of thrombosis and with the advantage of positive side effects during the treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12373918&dopt=Abstract raloxifene Evista



Evista
Estrogenic properties of raloxifene, but not tamoxifen, on D2 and D3 dopamine receptors in the rat forebrain.

Landry M, Levesque D, Di Paolo T.

Molecular Endocrinology and Oncology Research Center and Faculte de Pharmacie, Universite Laval, Sainte-Foy, Que., Canada.

The present study investigated the estrogenic specificity of the modulation of dopamine D(2) and D(3) receptors by comparing the effects of estradiol with tamoxifen or raloxifene. These compounds have estrogenic and/or antiestrogenic activity depending on the target tissue. Two weeks after ovariectomy of female rats, we observed a 60% decrease in the uterine weight, which was prevented by a replacement therapy of 2 weeks with 17beta-estradiol. A tamoxifen or raloxifene treatment of 2 weeks increased uterine weights by 35 and 15%, respectively, but significantly less than estradiol treatment. Ovariectomy decreased dopamine D(2) receptor specific binding (20%) in the dorsolateral part of the anterior striatum and these receptors were left unchanged in the other parts of the striatum as well as in the olfactory tubercle and the nucleus accumbens. 17beta-Estradiol and raloxifene, but not tamoxifen treatment prevented this decrease. Ovariectomy left dopamine D(3) receptor specific binding unchanged. However, estradiol and raloxifene treatment decreased dopamine D(3) receptor binding in the islands of Calleja, the core and shell of the nucleus accumbens and the dorsal part of the anterior striatum, compared with ovariectomized rats. Our results show that raloxifene, but not tamoxifen, has an agonist estrogenic activity on dopamine receptors. Furthermore, estradiol and raloxifene have opposite effects on specific binding to dopamine D(2) and D(3) receptors. Copyright 2002 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12411738&dopt=Abstract raloxifene Evista



Evista
Differential SERM effects on corepressor binding dictate ERalpha activity in vivo.

Webb P, Nguyen P, Kushner PJ.

Diabetes Center and the Department of Medicine, University of California, San Francisco, California 94143, USA.

Selective estrogen receptor modulators (SERMs) show differential effects upon ERalpha activation function 1 (AF-1). Tamoxifen allows strong ERalpha AF-1 activity, whereas raloxifene allows less and ICI 182,780 (ICI) allows none. Here, we show that blockade of corepressor histone de-acetylase (HDAC) activity reverses the differential inhibitory effect of SERMs upon AF-1 activity in MCF-7 cells. This suggests that differential SERM repression of AF-1 involves HDAC-dependent corepressors. Consistent with this, ICI and raloxifene are more potent than tamoxifen in promoting ERalpha-dependent sequestration of progesterone receptor-associated corepressors. Moreover, ICI and raloxifene are more efficient than tamoxifen in promoting ERalpha binding to the corepressor N-CoR in vivo and in vitro. An ERalpha mutation (537X) that increases N-CoR binding in the presence of all SERMs blocks AF-1 activity. An ERalpha mutation (L379R) that decreases N-CoR binding increases AF-1 activity in the presence of ICI and raloxifene and reverses the effect of the 537X mutation. The 537X and L379R mutations also alter the ligand preference of ERalpha action at AP-1 sites and C3 complement, an action that also involves AF-1. Together, our results suggest that differential SERM effects on corepressor binding can explain differences in SERM effects on ERalpha activity. We propose a model for differential effects of SERMs on N-CoR binding.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12482846&dopt=Abstract raloxifene Evista



Evista
Raloxifene administration in post-menopausal women with osteoporosis: effect of different BsmI vitamin D receptor genotypes.

Palomba S, Numis FG, Mossetti G, Rendina D, Vuotto P, Russo T, Zullo F, Nappi C, Nunziata V.

Department of Obstetrics & Gynaecology, University of Catanzaro, Catanzaro, Italy. stefanopalomba tin.it

BACKGROUND: The vitamin D receptor (VDR) gene polymorphism has been considered a factor influencing the effectiveness of the anti-osteoporotic treatments. The aim of this study was to correlate the effectiveness of raloxifene treatment in post-menopausal women with osteoporosis to BsmI VDR genotypes. METHODS: Between January and August 2000, 75 Italian osteoporotic women were enrolled and treated with raloxifene at a dose of 60 mg/day. At entry and after 1 year of treatment, lumbar bone mineral density (BMD), serum osteocalcin (OC) and urinary creatinine-corrected free deoxypyridinoline (DPD) levels were evaluated. DNA was extracted from blood and analysed with restriction endonuclease BsmI for VDR gene. RESULTS: After treatment, a significant increase in lumbar BMD and a significant reduction in serum OC and urinary DPD levels were observed. The percentage of change (mean +/- SD) in lumbar BMD, and in serum OC and urinary DPD levels was significantly different in homozygous bb (1.58 +/- 0.80, -5.15 +/- 2.36 and -7.71 +/- 2.89 for BMD, OC and DPD respectively) in comparison with BB (4.13 +/- 2.26, -13.59 +/- 4.68 and -15.16 +/- 4.65 for BMD, OC and DPD respectively) BsmI VDR genotypes. Heterozygous Bb VDR patients showed an intermediate percentage (mean +/- SD) of BMD, serum OC and urinary DPD change (2.49 +/- 1.54, -8.69 +/- 2.60 and -10.52 +/- 2.56 for BMD, OC and DPD respectively) not significantly different in comparison with homozygous BB and bb. CONCLUSIONS: In post-menopausal women with osteoporosis the effectiveness of raloxifene treatment on bone metabolism seems to be controlled by different BsmI VDR genotypes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12525466&dopt=Abstract raloxifene Evista



Evista
Differential effects of raloxifene, tamoxifen and fulvestrant on a murine mammary carcinoma.

Lamb CA, Helguero LA, Fabris V, Lucas C, Molinolo AA, Lanari C.

Instituto de Biologia y Medicina Experimental (Consejo Nacional de Investigaciones Cientificas y Tecnicas--CONICET), Buenos Aires, Argentina.

The purpose of this study was to evaluate the effect of the selective estrogen receptor modulators raloxifene and tamoxifen and of the pure antiestrogen fulvestrant on tumor growth and progesterone receptor (PR) expression in an experimental model of breast cancer. The effects of these compounds on cell proliferation were studied in primary cultures of a progestin-dependent mammary carcinoma tumor line, in the presence of medroxyprogesterone acetate (MPA) or 17-beta-estradiol (E2). In in vivo studies the tumor was inoculated subcutaneously in BALB/c female mice treated with 20 mg MPA depot. Raloxifene (12.5 mg/kg) or tamoxifen (5 mg/kg) were administered in daily doses or E2 silastic pellets (5 mg) were implanted. When the tumors reached about 25-50 mm2 MPA was removed in half of the animals. E2 induced complete tumor regressions, tamoxifen inhibited tumor growth in vivo while raloxifene disclosed proliferative effects in animals in which MPA had been removed. In vitro, E2 inhibited cell proliferation at concentrations higher than 10(-14)M. Raloxifene and fulvestrant, but not tamoxifen, partially reverted E2-induced inhibition. Fulvestrant and tamoxifen inhibited MPA-induced cell proliferation while raloxifene had a stimulatory effect. Tamoxifen and E2 increased, raloxifene induced no effect, and fulvestrant significantly decreased PR expression. In this study we provide evidence for differential effects of tamoxifen and raloxifene on experimental mammary tumors. Since raloxifene is under evaluation for use in breast cancer prevention, these results may have important clinical implications.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12779079&dopt=Abstract raloxifene Evista