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Results for “Estrogen Receptor Modulators”

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At least 343 records · Page 19Linked to original sources
PubMed2002

Solid-phase synthesis and investigation of benzofurans as selective estrogen receptor modulators.

A library of benzofurans was prepared by solid-phase synthesis methods, and several analogues were identified as potent ligands for the estrogen receptors ER-alpha and ER-beta, with some compounds having selectivity for ER-alpha. Analogues designed to more closely mimic Raloxifene were less effective. Certain benzofurans were effective in a bone pit assay, but were characterized as agonists in a MCF-7 breast tumor cell proliferation assay.

Benzofurans↗
PubMed2003

Selective estrogen receptor modulators as inhibitors of repopulation of human breast cancer cell lines after chemotherapy.

PURPOSE: Repopulation of surviving tumor cells between courses of chemotherapy might lead to effective drug resistance. Here we study inhibition of repopulation of hormone-responsive human breast cancer cell lines by selective estrogen receptor (ER) modulators (SERMs) during courses of chemotherapy. EXPERIMENTAL DESIGN: Hormone responsive breast cancer cell lines MCF-7 and T47D, and the ER- cell line MDA-231, were treated with either 4-hydroxy tamoxifen (4OHT) or arzoxifene during weekly courses of treatment with 5-fluorouracil (5-FU) or methotrexate (MTX). Clonogenic assays were performed to determine the overall survival of tumor cells after treatment with the SERMs alone, after one to three doses of 5-FU or MTX alone, and after 5-FU or MTX followed by each of the SERMs. RESULTS: Both SERMs inhibited the growth of ER+ cells MCF-7 and T47D but had no effect on the ER-cell line MDA-231. Arzoxifene was more effective than 4OHT. Between courses of treatment with either 5-FU or MTX, repopulation of ER+ cells was specifically inhibited by the SERMs, whereas repopulation of ER- MDA-231 was not affected. CONCLUSIONS: Arzoxifene and 4OHT can inhibit specifically the repopulation of ER+ breast cancer cells between courses of chemotherapy. Scheduling of short-acting SERMs between courses of chemotherapy has the potential to improve therapeutic index.

Antineoplastic Agents, Hormonal↗
PubMed2002

Differential response of estrogen receptors alpha and beta to SP500263, a novel potent selective estrogen receptor modulator.

We determined the differential response of a novel SERM, SP500263, on estrogen receptor (ER) alpha and the more recently cloned ER-beta. Because of the high homology of amino acid residues in the ligand-binding domain of ER-alpha and ER-beta, we were not surprised to find that SP500263 binds to both ERs equally well. In contrast, SP500263 acts as a strong estrogen agonist in a strictly ER-alpha-specific manner in U2OS osteosarcoma cell lines blocking the production of interleukin (IL) 6 and granulocyte macrophage colony-stimulating factor. SP500263 also blocked IL-6 production in primary bone cells. The mechanism of this inhibition is different from the classic estrogen stimulation involving an estrogen response element (ERE). SP500263 does not activate gene expression through an ERE. In contrast to the results observed in U2OS cells, SP500263 acts as a strong estrogen antagonist in an MCF-7 breast cancer proliferation assay. Therefore, SP500263 is a member of a series of next-generation SERMs with functional selectivity toward ER-alpha and a mixed agonist/antagonist profile in a bone cell assay versus a breast cancer assay. The panel of assays described herein allow for the development of receptor-specific ligands that may be further developed into novel pharmaceuticals with an improved profile for the treatments of osteoporosis and breast cancer.

Cells, Cultured↗
PubMed2001

Flexible estrogen receptor modulators: design, synthesis, and antagonistic effects in human MCF-7 breast cancer cells.

Although many series of estrogen receptor antagonists continue to be produced, the majority are direct structural analogues of existing modulators. To examine the tolerance of the estrogen receptor toward flexible ligands, a series of novel flexible estrogen receptor antagonists were prepared and their antiproliferative effects on human MCF-7 breast tumor cells investigated. Each of these compounds deviated from the traditional triphenylethylene backbone associated with common tamoxifen analogues through the introduction of a flexible methylene (benzylic) spacing group between one of the aryl rings and the ethylene group and through variations in the basic side chain moiety. The compounds prepared, when assayed in conjunction with a tamoxifen standard, demonstrated high potency in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity and high binding affinity. A computational study was undertaken to investigate the compounds' potential interactions with specific residues within the human estrogen receptor alpha ligand-binding domain (ER-LBD), predicting these compounds bind in an antiestrogenic fashion within the ER-LBD and interact with those important residues previously identified in the structures of ER-LBD agonist/antagonist cocrystals. These compounds further illustrate the eclectic nature of the estrogen receptor in terms of ligand flexibility tolerance.

Animals↗
PubMed2002

Oxytocin modulates estrogen receptor alpha expression and function in MCF7 human breast cancer cells.

Oxytocin (OT) inhibits the proliferation of MCF7 estrogen-dependent human breast cancer cells, via specific OT receptors (OTR). Besides this effect, we report that OT modulates the expression of estrogen receptor alpha (ERalpha) in MCF7 cells, both at mRNA and protein level. Since the first 24 h of OT treatment the ERalpha mRNA levels are down-regulated; in contrast, ERalpha protein expression decreases at a later time. The reduced number of ERalpha goes in parallel to a temporary increase in the binding affinity of these receptors as well as to a significant increase in their estradiol (E2)-induced transcription activity. The increase in both binding affinity and transcriptional activity of ERalpha likely balances the reduction in the number of ERalpha binding sites, ruling out the hypothesis that part of the OT contrasting effect on E2-induced cell proliferation could depend on the reduced E2 binding to MCF7 cells and supporting the hypothesis of an exclusively direct OT-antimitogenic effect. This is the first evidence that OT modulates the expression of ERalpha receptors in human neoplastic cells.

Breast Neoplasms↗
PubMed2001

The estimation and use of absolute risk for weighing the risks and benefits of selective estrogen receptor modulators for preventing breast cancer.

In order to weigh the risks and benefits of intervention with selective estrogen response modifiers for preventing breast cancer, one needs to consider the effects of intervention on several health outcomes. For example, tamoxifen was shown to reduce the risks of breast cancer and hip fracture while increasing the risks of endometrial cancer and cardiovascular end points, including stroke. One approach to weighing risks and benefits is to estimate the net effect of the intervention on the absolute risk of each of the relevant health outcomes. To estimate this net effect, one needs to know not only the relative risk from the intervention, but also the absolute risk of the health outcome in the absence of intervention. Intervention trials yield unbiased estimates of intervention relative risks, but data are usually too limited to estimate these relative risks precisely for subgroups or for rare health outcomes. Moreover, intervention trials are usually too small to provide data for developing a model for estimating the individualized absolute risk of various health outcomes in the absence of intervention. The model of Gail et al. for projecting the individualized risk of breast cancer, as modified for use in the Breast Cancer Prevention Trial, has been validated. To weigh various risks and benefits of interventions, there is a need for research to develop such models for a range of health outcomes.

Breast Neoplasms↗