Prevention of development of dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in the rat by the new nonsteroidal antiestrogen EM-800 (SCH57050)

Luo, Shouqi; Labrie, Claude; Bélanger, Alain; Candas, Bernard; Labrie, Fernand

doi:10.1023/a:1005928814521

Cited by 35 publications

(28 citation statements)

References 55 publications

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“…11,12 The present study extends these ®ndings by demonstrating that treatment of OVX rats with EM- HCl is at least as effective as estrogen replacement therapy in reverting obesity and its related lipid and glucoseainsulin abnormalities induced by OVX. Estrogen removal through OVX profoundly altered energy balance and lipid metabolism, as previously described by us and others 4 ± 7,19,20 In brief, OVX increased energy intake and food ef®ciency, which resulted in a larger deposition of body energy, mainly in the form of fat.…”

Section: Discussionsupporting

confidence: 74%

“…Such hypolipidemic actions have been reported recently for the prodrug EM-800. 12 In that study performed in fed animals, EM-800 was shown to be frankly hypotriglyceridemic, contrary to the neutral effect of EM-652.HCl observed here in fasted animals. It is most likely that the hypotriglycemic action of EM-652.HCl was masked in the present study by the rather long fasting period imposed on the animals before blood sampling.…”

Section: Discussioncontrasting

confidence: 52%

“…10 Despite its pure antiestrogenic activity in the mammary gland and endometrium, EM-652.HCl can be classi®ed as a selective estrogen receptor modulator, based on some`estrogen-like' properties of EM-800, the prodrug of EM-652, such as the prevention of bone loss and the lowering of plasma cholesterol and triglycerides. 11,12 In the course of studies on the action of EM-800, the prodrug of EM-652, collateral observations have suggested that these compounds may exert effects upon metabolic pathways associated with energy balance, glucose and lipid metabolism. 11,12 These observations, which suggested that the estrogen antagonist EM-652.HCl may exert effects that mimic, rather than antagonize, those of estrogen on energy and lipid metabolism, prompted us to undertake the present study to assess in detail such actions in a rat model.…”

Section: Introductionmentioning

confidence: 99%

“…11,12 In the course of studies on the action of EM-800, the prodrug of EM-652, collateral observations have suggested that these compounds may exert effects upon metabolic pathways associated with energy balance, glucose and lipid metabolism. 11,12 These observations, which suggested that the estrogen antagonist EM-652.HCl may exert effects that mimic, rather than antagonize, those of estrogen on energy and lipid metabolism, prompted us to undertake the present study to assess in detail such actions in a rat model. The experimental strategy consisted of evaluating the potential of EM-652.HCl to antagonize the effects of OVX on energy balance and lipid metabolism, and to compare its action with that of estrogen replacement.…”

Section: Introductionmentioning

confidence: 99%

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Effects of the estrogen antagonist EM-652.HCl on energy balance and lipid metabolism in ovariectomized rats

et al. 2000

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OBJECTIVE: The estrogen antagonist EM-652.HCl behaves as a highly potent and pure antiestrogen in human breast and uterine cancer cells. Because of its pure antiestrogenic activity in these cells, and because its prodrug, EM-800, reduces bone loss and decreases serum cholesterol and triglycerides in the rat, EM-652.HCl can be classi®ed as a pure selective estrogen receptor modulator (SERM). This study was conducted to assess the ability of EM-652.HCl to prevent obesity and abnormalities of lipid metabolism induced by ovariectomy in a rat model. DESIGN: Female rats were left intact or ovariectomized (OVX), and OVX rats were treated with placebo, estradiol (E 2 ), or EM-652.HCl for 20 days. At the end of the treatment period, parameters of energy balance and determinants of lipid metabolism were assessed. RESULTS: As expected, OVX increased energy intake, which in turn was accompanied by an increased energy, fat and protein gain and higher food ef®ciency. OVX also increased the triglyceride content of the liver and produced hypercholesterolemia and hyperinsulinemia. The weight of representative white adipose depots was higher in OVX than in intact rats. Lipoprotein lipase activity was higher in white adipose tissues of OVX rats than in those of intact animals, whereas its activity was lower in oxidative tissues (brown adipose and soleus muscle). Replacement therapy with a physiological dose of E 2 prevented most of the abnormalities in energy and lipid metabolism brought about by OVX, although its orexigenic effect was only partially corrected. In contrast, treatment of OVX rats with EM-652.HCl completely abolished OVX-induced obesity and its related abnormalities in lipid metabolism and glucoseainsulin homeostasis. CONCLUSION: These ®ndings demonstrate that EM-652.HCl can be considered as an effective agent to prevent OVXinduced obesity. The present study also shows that EM-652.HCl reduces cardiovascular risk factors associated with obesity such as hyperlipidemia and insulin resistance.

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Section: Discussionsupporting

confidence: 74%

Section: Discussioncontrasting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of the estrogen antagonist EM-652.HCl on energy balance and lipid metabolism in ovariectomized rats

et al. 2000

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“…Raloxifene (Ral), on the other hand, has less oestrogenic effects on uterus, but the same beneficial effects on bone and lipid metabolism (Delmas et al, 1997;Barrett-Connor et al, 1999;Cohen et al, 2000) while it is an antagonist of oestrogen action in the breast (Gottardis and Jordan, 1987;Cummings et al, 1999). Other SERMs like idoxifene (Idox) (Chander et al, 1991;Nuttall et al, 1998), GW 5638 (Willson et al, 1994(Willson et al, , 1997Connor et al, 2001) and EM 800 (Luo et al, 1998;Labrie et al, 1999;Martel et al, 2000) are different from tamoxifen and based on their activity in the rodent uterus are more closely related to raloxifene. Resveratrol (Res) does not formally belong to the SERM family, because it is a phytoestrogen found in the plants (Jang et al, 1997), however Res has similar in vivo characteristics to the SERMs (Mizutani et al, 2000;Bhat and Pezzuto, 2001;Wu et al, 2001).…”

mentioning

confidence: 99%

Molecular classification of selective oestrogen receptor modulators on the basis of gene expression profiles of breast cancer cells expressing oestrogen receptor α

Levenson¹,

Kliakhandler²,

Svoboda³

et al. 2002

Br J Cancer

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The purpose of this study was to classify selective oestrogen receptor modulators based on gene expression profiles produced in breast cancer cells expressing either wtERa or mutant 351 ERa. In total, 54 microarray experiments were carried out by using a commercially available Atlas cDNA Expression Arrays (Clontech), containing 588 cancer-related genes. Nine sets of data were generated for each cell line following 24 h of treatment: expression data were obtained for cells treated with vehicle EtOH (Control); with 10 79 or 10 78 M oestradiol; with 10 76 M 4-hydroxytamoxifen; with 10 76 M raloxifene; with 10 76 M idoxifene, with 10 76 M EM 652, with 10 76 M GW 7604; with 5610 75 M resveratrol and with 10 76 M ICI 182,780. We developed a new algorithm 'Expression Signatures' to classify compounds on the basis of differential gene expression profiles. We created dendrograms for each cell line, in which branches represent relationships between compounds. Additionally, clustering analysis was performed using different subsets of genes to assess the robustness of the analysis. In general, only small differences between gene expression profiles treated with compounds were observed with correlation coefficients ranged from 0.83 to 0.98. This observation may be explained by the use of the same cell context for treatments with compounds that essentially belong to the same class of drugs with oestrogen receptors related mechanisms. The most surprising observation was that ICI 182,780 clustered together with oestrodiol and raloxifene for cells expressing wtERa and clustered together with EM 652 for cells expressing mutant 351 ERa. These data provide a rationale for a more precise and elaborate study in which custom made oligonucleotide arrays can be used with comprehensive sets of genes known to have consensus and putative oestrogen response elements in their promoter regions.

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Evolution of Selective Estrogen and Androgen Receptor Modulators: Status of Current Therapy and New Drug Development

Wurz

DeGregorio

2011

Pharmaceutical Sciences Encyclopedia

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Prior to the discovery of nonsteroidal selective estrogen and androgen receptor modulators (SERMs and SARMs), the only available treatment modalities for conditions such as menopausal symptoms and postmenopausal osteoporosis in women, and the symptoms associated with hypogonadism in men, were steroid based. As this chapter will discuss, recent clinical trial data have shown that the long‐term use of hormone replacement therapy in postmenopausal women is associated with an increased risk of breast cancer and may increase the risk of coronary heart disease and dementia, contrary to the results of previous observational studies. There are also concerns that androgen replacement therapy in hypogonadal men may pose a risk to prostate health, in addition to the difficulties inherent with the delivery of steroidal androgens. Thus, there is now great interest in developing nonsteroidal, orally bioavailable therapies, that is, SERMs and SARMs, that can provide the respective benefits of estrogens and androgens while minimizing their associated side effects.

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Prevention of development of dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in the rat by the new nonsteroidal antiestrogen EM-800 (SCH57050)

Cited by 35 publications

References 55 publications

Effects of the estrogen antagonist EM-652.HCl on energy balance and lipid metabolism in ovariectomized rats

Effects of the estrogen antagonist EM-652.HCl on energy balance and lipid metabolism in ovariectomized rats

Molecular classification of selective oestrogen receptor modulators on the basis of gene expression profiles of breast cancer cells expressing oestrogen receptor α

Evolution of Selective Estrogen and Androgen Receptor Modulators: Status of Current Therapy and New Drug Development

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