Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new evista research articles will be listed here shortly after becoming available to us.
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Medical research on evista
Cancer Res. 2008 Jul 1; 68(13): 5226-35
Rizzo P, Miao H, D'Souza G, Osipo C, Yun J, Zhao H, Mascarenhas J, Wyatt D, Antico G, Hao L, Yao K, Rajan P, Hicks C, Siziopikou K, Selvaggi S, Bashir A, Bhandari D, Marchese A, Lendahl U, Qin JZ, Tonetti DA, Albain K, Nickoloff BJ, Miele L
High expression of Notch-1 and Jagged-1 mRNA correlates with poor prognosis in breast cancer. Elucidating the cross-talk between Notch and other major breast cancer pathways is necessary to determine which patients may benefit from Notch inhibitors, which agents should be combined with them, and which biomarkers indicate Notch activity in vivo. We explored expression of Notch receptors and ligands in clinical specimens, as well as activity, regulation, and effectors of Notch signaling using cell lines and xenografts. Ductal and lobular carcinomas commonly expressed Notch-1, Notch-4, and Jagged-1 at variable levels. However, in breast cancer cell lines, Notch-induced transcriptional activity did not correlate with Notch receptor levels and was highest in estrogen receptor alpha-negative (ERalpha(-)), Her2/Neu nonoverexpressing cells. In ERalpha(+) cells, estradiol inhibited Notch activity and Notch-1(IC) nuclear levels and affected Notch-1 cellular distribution. Tamoxifen and raloxifene blocked this effect, reactivating Notch. Notch-1 induced Notch-4. Notch-4 expression in clinical specimens correlated with proliferation (Ki67). In MDA-MB231 (ERalpha(-)) cells, Notch-1 knockdown or gamma-secretase inhibition decreased cyclins A and B1, causing G(2) arrest, p53-independent induction of NOXA, and death. In T47D:A18 (ERalpha(+)) cells, the same targets were affected, and Notch inhibition potentiated the effects of tamoxifen. In vivo, gamma-secretase inhibitor treatment arrested the growth of MDA-MB231 tumors and, in combination with tamoxifen, caused regression of T47D:A18 tumors. Our data indicate that combinations of antiestrogens and Notch inhibitors may be effective in ERalpha(+) breast cancers and that Notch signaling is a potential therapeutic target in ERalpha(-) breast cancers.
Clin Calcium. 2008 Jul; 18(7): 986-94
Ohta H
Changes in bone mass and estrogen levels occur in almost total sync with one another in a woman's lifecycle, with bone mass shown to increase in response to increases in estrogen in early adolescence and to decrease in response to decreases in estrogen during perimenopause. Therefore, menopause as it leads to estrogen deficiency is among the greatest causes of osteoporosis, and estrogen replacement therapy represents a highly rational therapeutic approach. However, it is of note that estrogen is associated with increased risk for breast cancer, while selective estrogen receptor modulators (SERM) are associated with no such risk and thus represent prophylactic and therapeutic agents for breast cancer. Of all SERMs, raloxifene is currently the only agent covered by insurance and available for the prophylaxis and treatment of osteoporosis. The current review therefore focuses on the role of estrogen and raloxifene in the management of osteoporosis.
Cancer Epidemiol Biomarkers Prev. 2008 Jun 26;
Eng-Wong J, Orzano-Birgani J, Chow CK, Venzon D, Yao J, Galbo CE, Zujewski JA, Prindiville S
BACKGROUND: Mammographic density is a risk factor for breast cancer. Mammographic density and breast magnetic resonance imaging (MRI) volume (MRIV) assess the amount of fibroglandular tissue in the breast. Mammographic density and MRIV can be modulated with hormonal interventions, suggesting that these imaging modalities may be useful as surrogate endpoint biomarkers for breast cancer chemoprevention trials. We evaluated the effect of raloxifene on mammographic density and MRIV in premenopausal women at increased risk for breast cancer.METHODS: Mammograms and MRI were obtained at baseline and after 1 and 2 years of 60 mg raloxifene by mouth daily for 27 premenopausal women. Mammographic percent dense area was calculated using a semiquantitative thresholding technique. T1-weighted spoiled gradient-echo MRI with fat suppression was used to determine breast MRIV using a semiautomatic method. Mean change in mammographic density and median change in MRIV were assessed by the Wilcoxon signed-rank test.RESULTS: No significant change in mammographic density was seen after treatment with raloxifene. Mean change after 1 year was 1% [95% confidence interval (95% CI), -3 to +5] and after 2 years was 1% (95% CI, -2 to +5). MRIV decreased on raloxifene. Median relative change in MRIV after 1 year was -17% (95% CI, -28 to -9; P = 0.0017) and after 2 years was -16% (95% CI, -31 to -4; P = 0.0004).CONCLUSIONS: In high-risk premenopausal women, mammographic density did not change on raloxifene, whereas MRIV significantly declined. Our findings suggest that MRIV is a promising surrogate biomarker in premenopausal women at increased risk for breast cancer and should be investigated further in breast cancer prevention trials. (Cancer Epidemiol Biomarkers Prev 2008;17(7):OF1-6).
Are the serum levels of sCD40L modified by raloxifene in postmenopausal women?
Eur J Obstet Gynecol Reprod Biol. 2008 Jun 24;
Oviedo PJ, Hermenegildo C, Novella S, Tarín JJ, Cano A
Intratumoral Estrogens and Estrogen Receptors in Human Non-Small Cell Lung Carcinoma.
Clin Cancer Res. 2008 Jun 25;
Niikawa H, Suzuki T, Miki Y, Suzuki S, Nagasaki S, Akahira J, Honma S, Evans DB, Hayashi SI, Kondo T, Sasano H
PURPOSE: The possible involvement of gender-dependent factors has been suggested in human non-small cell lung carcinomas (NSCLC), but their precise roles remain largely unclear. Therefore, we examined intratumoral estradiol concentrations in NSCLC to examine local actions of estrogens in NSCLC.EXPERIMENTAL DESIGN: Fifty-nine frozen specimens of NSCLC were available for liquid chromatography/electrospray tandem mass spectrometry to study intratumoral estradiol concentrations. In addition, A549 NSCLC cells stably expressing estrogen receptor (ER) alpha (A549 + ERalpha) or ERbeta (A549 + ERbeta) were used in vitro studies.RESULTS: Forty-three (73%) of 59 NSCLC showed higher concentration of estradiol in carcinoma tissues than the corresponding nonneoplastic lung tissues from the same patient, and intratumoral estradiol concentrations were significantly (P = 0.0002 and 2.2-fold) higher than the corresponding nonneoplastic lungs. The intratumoral concentration of estradiol was positively correlated with aromatase expression, tumor size, and Ki-67 status in ERalpha- or ERbeta-positive cases. In in vitro studies, estradiol significantly increased cell proliferation of A549 + ERalpha or A549 + ERbeta, which was significantly suppressed by selective ER modulators, tamoxifen or raloxifene. Both A549 + ERalpha and A549 + ERbeta cells expressed aromatase. The cell proliferation level in these cells was significantly increased under treatment with testosterone, and it was inhibited by addition of the aromatase inhibitor letrozole.CONCLUSIONS: These results suggest that estradiol is locally produced in NSCLC mainly by aromatase and plays an important role in the growth of ERalpha- or ERbeta-positive NSCLC. Therefore, use of selective ER modulators and/or aromatase inhibitors may be clinically effective in NSCLC that are positive for both ER and aromatase.
Breast Cancer. 2008; 15(3): 185-91
Ashikari RH, Ashikari AY, Kelemen PR, Salzberg CA
Breast cancer is the most common malignant tumor among females in the USA, with one out of eight American females developing breast cancer in their lifetimes. The latest studies [1] show that 212,920 new cases of invasive cancer developed in 2006, which is 2.5 times more common than the incidence of lung cancer, and that 40,970 females will die from this disease each year. Therefore, awareness of this cancer is an important health issue, with more women beginning to assess their risk of breast cancer, either informally or with instruments such as the GAIL model [2]. The availability of genetic testing for BRCA-1 and BRCA-2 has revealed many women who are at significantly increased risk. Many aggressive surveillance programs have been developed using advanced MRI and ultrasound, and reductions in breast cancer risk of 50% or more have been proven using chemoprevention strategies with tamoxifen and raloxifene. However, many women are starting to seriously consider prophylactic mastectomy for near-total reduction of breast cancer risk. At our institution, we have developed a procedure for prophylactic subcutaneous mastectomy via an inframammary incision that spares the nipple and is combined with immediate silicone implant reconstruction with the assistance of Alloderm. In this article we will describe the procedure and some of the important issues surrounding its implementation from our experience.
Raloxifene protects endothelial cell function against oxidative stress.
Br J Pharmacol. 2008 Jun 23;
Wong CM, Yung LM, Leung FP, Tsang SY, Au CL, Chen ZY, Yao X, Cheng CH, Lau CW, Gollasch M, Huang Y
Background and purpose:Maintaining a delicate balance between the generation of nitric oxide (NO) and removal of reactive oxygen species (ROS) within the vascular wall is crucial to the physiological regulation of vascular tone. Increased production of ROS reduces the effect and/or bioavailability of NO, leading to an impaired endothelial function. This study tested the hypothesis that raloxifene, a selective oestrogen receptor modulator, can prevent endothelial dysfunction under oxidative stress.Experimental approach:Changes in isometric tension were measured in rat aortic rings. The content of cyclic GMP in aortic tissue was determined by radioimmunoassay. Phosphorylation of endothelial NOS (eNOS) and Akt was assayed by Western blot analysis.Key results:In rings with endothelium, ACh-induced relaxations were attenuated by a ROS-generating reaction (hypoxanthine plus xanthine oxidase, HXXO). The impaired relaxations were ameliorated by acute treatment with raloxifene. HXXO suppressed the ACh-stimulated increase in cyclic GMP levels; this effect was antagonized by raloxifene. The improved endothelial function by raloxifene was abolished by ICI 182,780, and by wortmannin or LY294002. Raloxifene also protected endothelial cell function against H(2)O(2). Raloxifene increased the phosphorylation of eNOS at Ser-1177 and Akt at Ser-473; this effect was blocked by ICI 182,780. Finally, raloxifene was not directly involved in scavenging ROS, and neither inhibited the activity of xanthine oxidase nor stimulated that of superoxide dismutase.Conclusion and implications:Raloxifene is effective against oxidative stress-induced endothelial dysfunction in vitro through an ICI 182,780-sensitive mechanism that involves the increased phosphorylation and activity of Akt and eNOS in rat aortae.British Journal of Pharmacology advance online publication, 23 June 2008; doi:10.1038/bjp.2008.262.
Effects of estrogen and estrogenic compounds on cognition in ovariectomized rats.
Climacteric. 2008 Jun; 11(3): 212-20
Wu J, Zhu Y, Wu J
OBJECTIVES: To evaluate the effects of estrogen and estrogenic compounds on cognition in ovariectomized rats. METHODS: Female Sprague-Dawley rats (3-5 months old) weighing 250-300 g were randomly divided into seven groups: Sham, ovariectomized (OVX), OVX plus estradiol valerate, OVX plus ipriflavone, OVX plus raloxifene, OVX plus tibolone, OVX plus low-dose estradiol valerate and ipriflavone. All treatments were given orally for 3 months; whereas the drug groups received indicated drugs, the Sham and OVX control groups received saline. The escape latency of rats was tested by the Morris water maze test and the expression of amyloid precursor protein (APP) in hippocampus was determined by reverse transcription polymerase chain reaction. The level of serum estradiol and the diameter of the endometrial gland and the thickness of endometrium were also evaluated. RESULTS: The latency of the OVX group was noticeably longer than that of the Sham group, and the latency of all treatment groups was lower than that of OVX rats. The expression of APP mRNA in the hippocampii of OVX rats was significantly increased relative to that in Sham rats; interestingly, expression of APP in treatment groups was significantly reduced relative to OVX rats. CONCLUSIONS: Our data indicate that estrogenic compounds can antagonize cognitive impairment and that all these compounds cause only mild stimulation on the endometrium compared to estrogen. Inhibition of APP expression in the hippocampus may account for, at least partially, the protective effects of these estrogenic compounds against cognitive defects. Our data suggest that estrogenic compounds (raloxifene, tibolone and ipriflavone) may be a promising approach to antagonize cognitive impairment in postmenopausal women.
Preventing breast cancer in high-risk women, 2008.
Oncology (Williston Park). 2008 May; 22(6): 666-73; discussion 679, 682, 684
Vogel VG
Several large, prospective trials have evaluated tamoxifen compared with placebo for breast cancer risk reduction in women at increased risk for breast cancer. Analysis of the large, prospective breast cancer risk-reduction trials that used tamoxifen estimated that tamoxifen decreased breast cancer incidence by 38% on average and estrogen receptor-positive tumors by 48%. Tamoxifen is known to have several serious side effects, including uterine malignancy, thromboembolic events, cataracts, and menopausal symptoms, that have limited its usefulness in the risk-reduction setting. Raloxifene (Evista) is a benzothiophene selective estrogen-receptor modulator that has antiestrogenic effects on breast and endometrial tissue as well as estrogenic effects that are similar to but distinct from tamoxifen. Among postmenopausal women who are at increased risk for breast cancer, raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer but appears to be less effective than tamoxifen in reducing the risk of in situ breast cancer. Raloxifene causes less benign and malignant uterine changes and fewer thromboembolic events than tamoxifen. Symptomatic side effects are comparable for the two drugs. Raloxifene is more appropriate than tamoxifen for reduction of breast cancer risk among postmenopausal women at increased risk for breast cancer.
J Endocrinol Invest. 2008 May; 31(5): 416-21
Fernández-García D, Muñoz-Torres M, Mezquita-Raya P, de la Higuera M, Alonso G, Reyes-García R, Ochoa AS, Ruiz-Requena ME, Luna JD, Escobar-Jiménez F
Previous in vitro studies suggest that the anti-resorptive effect of raloxifene might be mediated by changes in several cytokines involved in the bone remodeling process. In this context, the osteoprotegerin (OPG)- receptor activator of NF kappa B ligand (RANKL) system is considered a key component in the osteoclastogenesis regulation. The aim of this study was to determine the effects of raloxifene treatment on serum concentrations of OPG, receptor RANKL and its relationship with biochemical markers of bone turnover and bone mineral density (BMD) in previously untreated women with post-menopausal osteoporosis. We selected 47 post-menopausal women (mean age 63+/-7 yr) with densitometric criteria of osteoporosis. We determined at baseline, 3, 6, and 12 months anthropometric parameters, biochemical markers of bone turnover, serum levels of 25(OH) D, serum levels of OPG and RANKL. BMD (dual-energy x-ray absorptiometry) in lumbar spine (LS) femoral neck and total hip was measured at baseline and 12 months after raloxifene (60 mg/day) treatment. Serum levels of OPG decreased in the 3rd and 6th month of treatment (p