Concentrations of 2-methoxyoestrogens in human serum measured by a heterologous immunoassay with an 125I-labelled ligand

Berg, D.K.; Sonsalla, R.; Kuß, E.

doi:10.1530/acta.0.1030282

Cited by 103 publications

(72 citation statements)

References 8 publications

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“…Both compounds induced COX-2; COX-2 was induced at concentrations as low as 25 nM 2-methoxyestradiol. Although the physiologic significance of this finding is uncertain, 30 nM 2-methoxyestrogens has been detected in the serum of pregnant females (56).…”

Section: Discussionmentioning

confidence: 96%

Microtubule-interfering Agents Stimulate the Transcription of Cyclooxygenase-2

Subbaramaiah

Hart

Norton

et al. 2000

Journal of Biological Chemistry

272

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Section: Discussionmentioning

confidence: 96%

Microtubule-interfering Agents Stimulate the Transcription of Cyclooxygenase-2

Subbaramaiah

Hart

Norton

et al. 2000

Journal of Biological Chemistry

272

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“…Consequently, 2ME has been widely viewed as a ''good estrogen,'' exerting growth-inhibitory effects on breast cancer (4). Although serum concentrations of 2ME (25-55 pg/mL) in women are comparable to that of E 2 (40-80 pg/mL), as much as 4,000 pg/ mL of 2ME has been reported in pregnant women (6).…”

mentioning

confidence: 84%

Physiologic Levels of 2-Methoxyestradiol Interfere with Nongenomic Signaling of 17β-Estradiol in Human Breast Cancer Cells

Vijayanathan

Venkiteswaran

Nair

et al. 2006

Clinical Cancer Research

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Purpose:The purpose of this investigation is to determine the effects of physiologic levels (10-50 nmol/L) of 2-methoxyestradiol (2ME) on the growth of estrogen receptor (ER)^positive breast cancer cells and provide insights into its mechanism(s) of action. Experimental Design: Using the ERa-positive breast cancer cells, we studied the effects of 2ME on cell proliferation and cell signaling. Our hypothesis is that 17h-estradiol (E 2 ) and 2ME can affect shared cell signaling pathways, leading to different outcomes in cell proliferation, depending on the absence/presence of E 2 .Results: E 2 stimulated the growth of MCF-7 andT-47 D cells and induced Akt phosphorylation, a nongenomic signaling pathway. In the absence of E 2 , 10 to 50 nmol/L of 2ME enhanced cell growth and Akt phosphorylation. However, in the presence of E 2 , 2ME inhibited E 2 -induced cell growth and prevented E 2 -induced Akt phosphorylation. Confocal microscopic studies showed that 2ME inhibited subcellular distribution of ERa in response to E 2 in MCF-7 and T-47D cells. 2ME also down-regulated E 2 -induced increases in cyclic AMP and ornithine decarboxylase activity. In addition, treatment of MCF-7 cells with 2ME in the presence of E 2 resulted in a decrease in ERa level by 72 hours. Accelerated down-regulation of ERa may contribute to growth inhibition in the presence of E 2 /2ME combinations. In contrast, a concentration of up to 2.5 Amol/L 2ME had no effect on the growth of ER-negative SK-BR-3 cells, either in the presence or absence of E 2 . Conclusions: Our results provide evidence for the nongenomic action of 2ME in ER-positive cells. In the presence of E 2 , 2ME suppressed E 2 -induced cell growth, Akt signaling, and generation of cyclic AMP, whereas it acted as an estrogen in the absence of E 2 . The intriguing growthstimulatory and growth-inhibitory effects of 2ME on breast cancer cells suggests the need for its selective use in patients.17h-Estradiol (E 2 ), estrone (E 1 ), and some of its biologically active metabolites not only regulate the physiology of the mammary glands, but also affect the development of breast cancer. Enzymes involved in multiple pathways of biosynthesis and the metabolism of endogenous estrogens contribute to the etiology of human breast cancer (1, 2). Distinct metabolic pathways are responsible for conversion of E 2 or E 1 to derivatives hydroxylated at the C-2 or C-4 positions (catechol estrogens) or to the 16a position (16a-hydroxy-E1; refs. 3, 4). Catechol estrogens are further converted to methoxyestrogens by catechol-O-methyltransferase -mediated methylation.

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“…The affinity of 2MEO for ER (K i f100-300 nmol/L) has been established using radioligand binding assays on rat uterine cytosol, which is rich in ERa (18,37) and similar affinity estimates have been obtained in MCF7 cells (35). Endogenous plasma levels of 2MEO are greatest in the last 3 weeks of pregnancy (f10 nmol/L) and otherwise are <0.1 nmol/L (38). There is little likelihood that endogenous 2MEO has significant physiologic actions through binding to ER.…”

Section: Introductionmentioning

confidence: 99%

2-Methoxyestradiol Is an Estrogen Receptor Agonist That Supports Tumor Growth in Murine Xenograft Models of Breast Cancer

Sutherland

Schuliga

Harris

et al. 2005

Clinical Cancer Research

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Purpose: 2-Methoxyestradiol (2MEO) is being developed as a novel antitumor agent based on its antiangiogenic activity, tumor cell cytotoxicity, and apparent lack of toxicity. However, pharmacologic concentrations of 2MEO bind to estrogen receptors (ER). We have therefore examined the ER activity of 2MEO.Experimental Design: Estrogenic actions of 2MEO were evaluated by changes in gene expression of the ER-positive (MCF7) breast tumor cell line and, in vivo, estrogenicity was assessed in breast tumor xenograft models and by measuring endocrine responses in uterus and liver.Results: In the ER-positive breast tumor cell line (MCF7), microarray experiments revealed that 269 of 279 changes in gene expression common to 2MEO and estradiol were prevented by the ER antagonist, ICI 182,780. Changes in the expression of selected genes and their sensitivity to inhibition by ICI 182,780 were confirmed by quantitative reverse transcription-PCR measurement. Activation of ER in MCF7 cells by 2MEO was further confirmed by stimulation of an estrogen response element -dependent reporter gene that was blocked by ICI 182,780 (1 Mmol/L). Doses of 2MEO (15-150 mg/kg) that had no antitumor efficacy in either nu/nu BALB/c or severe combined immunodeficient mice bearing ER-negative MDA-MB-435 tumors had uterotropic and hepatic estrogen-like actions. In female nu/nu BALB/c mice inoculated with the estrogen-dependent MCF7 tumor cells, 2MEO (50 mg/kg/d) supported tumor growth.Conclusions: Tumor growth enhancement by 2MEO at doses generating serum levels (100-500 nmol/L) that have estrogenic activity suggests that a conservative approach to the further clinical evaluation of this agent should be adopted and that its evaluation in breast cancer is inappropriate.

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Concentrations of 2-methoxyoestrogens in human serum measured by a heterologous immunoassay with an 125I-labelled ligand

Cited by 103 publications

References 8 publications

Microtubule-interfering Agents Stimulate the Transcription of Cyclooxygenase-2

Microtubule-interfering Agents Stimulate the Transcription of Cyclooxygenase-2

Physiologic Levels of 2-Methoxyestradiol Interfere with Nongenomic Signaling of 17β-Estradiol in Human Breast Cancer Cells

2-Methoxyestradiol Is an Estrogen Receptor Agonist That Supports Tumor Growth in Murine Xenograft Models of Breast Cancer

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