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In vitro study of the effect of raloxifene on lipid metabolism compared with tamoxifen.

Hozumi Y, Kawano M, Jordan VC.

Robert H Lurie Comprehensive Cancer Center, Northwestern University Medical School, 303 E Chicago Avenue, Olson Pavilion 8258, Chicago, Illinois 60611, USA. y-hozumi jichi.ac.jp

OBJECTIVE: Tamoxifen and raloxifene, selective estrogen receptor modulators, decrease serum concentrations of total cholesterol; however, the effect of these drugs on triglyceride metabolism is unclear. In the present study, we investigated the in vitro effect of raloxifene on lipid metabolism and compared it with that of tamoxifen. DESIGN AND METHODS: Intracellular concentrations of total cholesterol and triglyceride in HepG2 cells were measured by an enzymatic method after tamoxifen or raloxifene treatment with or without oleic acid and with or without very low density lipoprotein. RESULTS: Intracellular concentrations of total cholesterol and triglyceride without oleic acid or very low density lipoprotein were not significantly different after treatment with tamoxifen or raloxifene. In contrast, although raloxifene with oleic acid did not increase the intracellular concentrations of triglyceride, tamoxifen treatment in the presence of oleic acid or very low density lipoprotein significantly increased (P<0.05) the triglyceride concentrations. CONCLUSION: The present study suggests that raloxifene does not increase intracellular triglyceride in the presence of oleic acid or very low density lipoprotein, in contrast to tamoxifen. Therefore, raloxifene might be safer than tamoxifen for treating patients with unstable triglyceride levels or a history of hypertriglyceridemia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11022187&dopt=Abstract raloxifene Evista



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Raloxifene and estrogen inhibit neointimal thickening after balloon injury in the carotid artery of male and ovariectomized female rats.

Kauffman RF, Bean JS, Fahey KJ, Cullinan GJ, Cox DA, Bensch WR.

Cardiovascular Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.

The effects of raloxifene and 17alpha-ethinyl estradiol (EE2) on intimal thickening in response to balloon injury were tested in male and ovariectomized female rats. In male rats, oral raloxifene and EE2, administered either by gavage or in the diet, inhibited arterial intimal thickening in response to balloon injury to a maximum of approximately 60 and 50%, respectively. The effect of oral raloxifene to decrease cholesterol was observed at doses (> or = 3 mg/kg/day) higher than those required to inhibit intimal thickening (> or = 0.03 mg/kg/day). Coadministration of the estrogen receptor antagonist, ICI 182,780 (5 mg/kg/day, s.c.), blocked the inhibition of balloon injury by raloxifene and EE2. Direct adventitial delivery of raloxifene (0.03 mg/kg/day) and EE2 (0.001 mg/kg/day) to the vascular wall inhibited intimal thickening by 63 and 53%, respectively. In ovariectomized female rats, oral raloxifene (0.01-3.0 mg/kg/day) and EE2 (0.08 mg/kg/day) inhibited intimal thickening to a maximum of 32 and 60%, respectively. Together, these data suggest that raloxifene and EE2, inhibit balloon arterial injury in the rat through direct effects on the vascular wall that involve the estrogen receptor and are at least partially independent of serum cholesterol.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11026646&dopt=Abstract raloxifene Evista



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Distinct mechanisms of action of selective estrogen receptor modulators in breast and osteoblastic cells.

Nuttall ME, Stroup GB, Fisher PW, Nadeau DP, Gowen M, Suva LJ.

Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. Mark_E_Nuttall sbphrd.com

Raloxifene and idoxifene are selective estrogen receptor modulators (SERMs) that exhibit tissue-specific agonist or antagonist properties via interactions with the estrogen receptor (ER). Both compounds are similarly osteoprotective in the ovariectomized rat in vivo as assessed by measurement of bone mineral density, urinary pyridinium cross-links, and serum osteocalcin, suggesting a similar mechanism of action. However, we have identified a fundamental difference in this mechanism via the estrogen response element (ERE) in osteoblast-like cells. With the use of ERE-luciferase reporter constructs, raloxifene, like the complete ER-antagonist ICI-182780, acts as an antagonist via the ERE in osteoblastic cells. In contrast, idoxifene, like 17beta-estrogen itself and 4-OH-tamoxifen, acts as an agonist in osteoblastic cells via an ER/ERE-mediated mechanism. Both ICI-182780 and raloxifene inhibited the ERE-dependent agonist activity of 17beta-estradiol and idoxifene in osteoblastic cells. In contrast, in breast cells, raloxifene, idoxifene, 4-OH-tamoxifen, and ICI-182780 had no agonist activity and, indeed, raloxifene and idoxifene were potent antagonists of ERE-mediated 17beta-estradiol action, indicating an ERE-dependent mode of action in these cells. Although these SERMs exhibit a similar antagonist activity profile in breast cells, they can be distinguished mechanistically in osteoblastic cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11029302&dopt=Abstract raloxifene Evista



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Update on raloxifene to prevent endometrial-breast cancer.

Goldstein SR.

New York University School of Medicine, 530 First Avenue Suite 10N, New York, NY 10016, USA. steven.goldstein med.nyu.edu

In the mid 1980s when tamoxifen was shown to be associated with endometrial neoplasia there was a renewed interest in another SERM compound, raloxifene. Experimental animal data suggested that raloxifene did not stimulate the endometrium as tamoxifen does while having similar anti-oestrogenic effects in breast tissue as tamoxifen. Clinical data has now shown that raloxifene does not stimulate the endometrium in postmenopausal women. It results in no hyperplasia, no increase in endometrium thickness or polyp formation and virtually no proliferation. Further studies are necessary to see if long-term raloxifene use will reduce the risk of endometrial cancer. In studies of raloxifene as treatment for osteoporosis, when viewed as a secondary endpoint there was a significant reduction in risk of new onset breast cancer. Further studies with breast cancer as a primary endpoint are ongoing (the STAR Trial).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11056320&dopt=Abstract raloxifene Evista



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The selective oestrogen receptor modulators idoxifene and raloxifene have fundamentally different cell-specific oestrogen-response element (ERE)-dependent/independent mechanisms in vitro.

Nuttall ME, Fisher PW, Suva LJ, Gowen M.

Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, UW2109, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA. mark_e_nuttall sbphrd.com

Idoxifene and raloxifene are selective oestrogen receptor modulators (SERMs) that by definition exhibit tissue-specific agonist or antagonist properties via interactions with the oestrogen receptor (ER). Idoxifene acts as an oestrogen agonist in osteoblastic cells via an ER/ERE-mediated mechanism. In contrast, raloxifene is an antagonist via the ERE in osteoblastic cells. Like the pure antagonist ICI 182,780, raloxifene inhibited the potent agonist activity of both 17beta-oestradiol and idoxifene through the ERE whereas idoxifene had no effect on the agonist activity of 17beta-oestradiol via the ERE. In breast cancer cells, both raloxifene and idoxifene were potent antagonists of ERE-mediated 17beta-oestradiol action suggesting an ERE-dependent mechanism of action for both ligands in these cells. Therefore, these SERMs exhibit cell-specific ERE-dependent and -independent mechanisms of action.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11056323&dopt=Abstract raloxifene Evista



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How to manage the menopause following therapy for breast cancer. is raloxifene a safe alternative?

Sismondi P, Biglia N, Roagna R, Ponzone R, Ambroggio S, Sgro L, Cozzarella M.

Department of Gynecological Oncology, University of Turin, Mauriziano 'Umberto I' Hospital, c.so G. Ferraris 122, 10128, Turin, Italy. psismondi mauriziano.it

Raloxifene is a selective oestrogen receptor modulator (SERM) that has anti-oestrogenic effects on breast and endometrial tissue and oestrogenic actions on bone, lipid metabolism and blood clotting. In postmenopausal women raloxifene decreases bone turnover and increases bone mineral density, reducing the incidence of vertebral fractures. Unlike tamoxifen, raloxifene does not cause endometrial hyperplasia or cancer, as demonstrated by endometrial monitoring with ultrasonography and biopsy during treatment. Evidence suggests that raloxifene lowers total low-density lipoprotein cholesterol levels behaving like oestrogens, but does not increase high-density lipoprotein cholesterol levels. In randomised clinical trials on postmenopausal women with osteoporosis, raloxifene reduced the risk of newly diagnosed ER-positive invasive breast cancer by 76% during a median of 40 months of treatment. However, raloxifene does not alleviate early menopausal symptoms, such as hot flushes and urogenital atrophy, and may even exacerbate some of them. In conclusion, raloxifene may be an alternative for the prevention of long-term effects of oestrogen deficiency (osteoporosis and heart diseases) in women with previous breast cancer not having hot flushes. For symptomatic patients, the association of raloxifene with different drugs which have demonstrated efficacy in the control of vasomotor symptoms is now under evaluation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11056328&dopt=Abstract raloxifene Evista