Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2-Methoxyestradiol (2-ME), an endogenous estrogen metabolite which disrupts microtubule function, has been shown to inhibit proliferating cells in vitro and suppress certain murine tumors in vivo. In vitro screening has determined that breast cancer cell lines are most sensitive to inhibition by 2-ME. Additionally, 2-ME has been shown to inhibit angiogenesis in vitro. We tested whether 2-ME suppresses cytokine-induced angiogenesis in vivo and inhibits growth of a human breast carcinoma in severe combined immunodeficient mice. A model of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF)-induced corneal neovascularization in C57BL/6 mice was used to evaluate the antiangiogenic effects of 2-ME and other microtubule inhibitors such as Taxol, vincristine, and colchicine. 2-ME (150 mg/kg p.o., n = 20) inhibited bFGF and VEGF-induced neovascularization by 39% and 54%, respectively. Taxol (6 mg/kg i.p., n = 17) inhibited bFGF and VEGF-induced neovascularization by 45% and 37%, respectively. Vincristine (0.2 mg/kg i.p., n = 8) and colchicine (0.25 mg/kg i.p., n = 8) had no effect. Treatment with 2-ME (75 mg/kg p.o., n = 9) for 1 month suppressed the growth of a human breast carcinoma in mice by 60% without toxicity. Recognition of the antiangiogenic and antitumor properties of 2-ME and Taxol may be crucial in planning clinical applications to angiogenesis-dependent diseases.
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PMID:Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. 898 45

2-Methoxyestradiol. 2-Methoxyestradiol (2-ME) is an endogenous estradiol metabolite that disrupts microtubule function, suppresses murine tumors, and inhibits angiogenesis. Since some microtubule inhibitors have been shown to alter radiosensitivity, we have evaluated 2-ME as a radiation enhancer in vitro. H460 human lung cancer cells were plated, treated with 2-ME for 24 h, and irradiated; then colony-forming ability was assessed. The radiation dose enhancement ratios (DERs) using this protocol were 1.3, 1.8 and 2.1 for 1, 1.5 and 2 microM 2-ME, respectively. Using a single-cell plating protocol, the respective DERs were 1.2, 1.5 and 1.8. The parent compound of 2-ME, beta-estradiol, did not enhance radiation effects at equally cytotoxic doses. Isobologram analysis showed that 1 microM 2-ME was additive with radiation, but that 1.5 and 2 microM were synergistic. Cell cycle analysis showed a dose-dependent increase in the percentage of cells in the radiosensitive G(2)/M phase after a 24-h treatment with 2-ME; a threefold increase in the percentage of cells in G(2)/M phase was observed using 2 microM 2-ME. Treatment with 2 microM 2-ME almost completely inhibited repair of sublethal damage (SLD) as shown using split-dose recovery. Radiosensitive, repair-deficient murine SCID (severe combined immunodeficient) cells did not show enhancement of radiation effects with 2 microM 2-ME, but enhancement was observed in the wild-type parental cells (CB-17). SCID cells complemented with human DNA-dependent protein kinase restored radioenhancement by 2-ME. In addition, MCF-7 breast cancer cells were also radiosensitized by 2 microM 2-ME (DER = 2.1). These data suggest that 2-ME is a potential radiation sensitizer, in addition to its previously reported antitumor and antiangiogenic properties. We have verified the antiangiogenic activity of 2-ME in vitro using human endothelial cells. Based on these results, we hypothesize that the mechanism of radiation enhancement may involve redistribution of cells into G(2)/M phase by 2-ME, and that the resulting population of cells is repair-deficient and thus radiosensitive.
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PMID:Enhancement of radiation effects in vitro by the estrogen metabolite 2-methoxyestradiol. 1076 Sep 97

2-Methoxyestradiol (2ME(2)) is an endogenous metabolite of 17beta-estradiol (E(2)) that arises from the hydroxylation and subsequent methylation at the 2-position. In vitro 2ME(2) inhibits a large variety of tumor and nontumor cell lines from diverse origins, as well as several stages of the angiogenic cascade. In vivo it has been shown to be a very effective inhibitor of tumor growth and angiogenesis in numerous models. Although various molecular targets have been proposed for this compound, the mechanism of action is still uncertain. As this molecule emerges as a drug candidate it is important to assess the estrogen receptors (ERs) as molecular targets for 2ME(2). The purpose of this study was to investigate whether 2ME(2) is able to engage ERs as an agonist and whether its antiproliferative activities are mediated through ERs. We confirm that 2ME(2) has a lower binding affinity for ERalpha as compared with E(2) and other E(2) metabolites and antagonists, and we demonstrate that the affinity of 2ME(2) for ERbeta is even lower. When assessed in the presence of galangin, a cytochrome P450 enzyme inhibitor, at concentrations at which 2ME(2) interacts with ERalpha in an in vitro binding assay, it does not stimulate the proliferation of an estrogen-dependent breast carcinoma cell line. Similar IC(50) values for inhibition of proliferation and induction of apoptosis are obtained in estrogen-dependent and estrogen-independent human breast cancer cell lines, irrespective of the expression of ERalpha and ERbeta. Moreover, the estrogen antagonist ICI 182,780 does not inhibit the antiproliferative activity of 2ME(2). In E(2)-responsive cells such as MCF-7 and human umbilical vascular endothelial cells, high levels of E(2) inhibit the antiproliferative activity of ICI 182,780 but not of 2ME(2). Collectively, these results suggest that 2ME(2) is distinct among estradiol metabolites because of its inability to engage ERs as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of ERalpha and ERbeta.
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PMID:2-Methoxyestradiol inhibits proliferation and induces apoptosis independently of estrogen receptors alpha and beta. 1209 76

Estrogens occurring naturally in the body are metabolized to catecholestrogens (2- and 4-hydroxyestradiol) by the cytochrome P450 enzymes. 2-Hydroxy catecholestrogens are further metabolized by catechol-O-methyltransferase to 2-methoxyestradiol, which is known to be protective against tumor formation. 2-Methoxyestradiol exhibits potent apoptotic activity against rapidly growing tumor cells. It also possesses antiangiogenic activity through a direct apoptotic effect on endothelial cells. Other molecular mechanisms, including microtubule stabilization by inhibition of the colchicine-binding site, have been reported. The exact mechanism of action of 2-methoxyestradiol is still unclear, but it has been shown to be effective in preventing tumor growth in a variety of cell lines. 2-Methoxyestradiol also possesses cardioprotective activity by inhibiting vascular smooth muscle cell growth in arteries. It has a lower binding affinity for estrogen receptor alpha compared with that of estradiol, and its affinity for estrogen receptor beta is even lower than that of estrogen receptor alpha, thus it has minimal estrogenic activity. 2-Methoxyestradiol is distinct because of its inability to engage estrogen receptors as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of estrogen receptors alpha and beta. A phase I clinical trial of 2-methoxyestradiol 200, 400, 600, 800, and 1,000 mg/day in 15 patients with breast cancer showed significant reduction in bone pain and analgesic intake in some patients, with no significant adverse effects. Another phase I study of 2-methoxyestradiol 200-1,000 mg/day in combination with docetaxel 35 mg/m2/week for 4-6 weeks performed in 15 patients with advanced refractory metastatic breast cancer showed no serious drug-related adverse effects. A phase II randomized, double-blind trial of 2-methoxyestradiol 400 and 1,200 mg/day in 33 patients with hormone-refractory prostate cancer showed that it was well tolerated and showed prostate specific antigen stabilizations and declines. We have started a phase I clinical trial to explore dosages greater than 1,000 mg/day.
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PMID:2-Methoxyestradiol, a promising anticancer agent. 1258 5

2-Methoxyestradiol (2ME) is an endogenous estradiol metabolite, which acts antiproliferative in various tumor cell lines independent of the hormone receptor status. We investigated whether combinations of 2ME with various chemotherapeutic or endocrine compounds may result in an additive effect on the proliferation of human breast cancer cells. The breast cancer cell lines MCF-7 (receptor-positive), BM (receptor-negative) and a MCF-7 line transfected with the aromatase gene were used. All cell lines were incubated in the concentration range of 0.8 microM to 25 microM with 2ME alone and in equimolar combinations with the following compounds: epirubicine, daunorubicine, paclitaxel, docetaxel, carboplatin, vinorelbine, 5-fluorouracil, mafosfamide and 4-OH tamoxifen. The effect of letrozole and 2ME alone and in equimolar combinations was tested in the concentration range of 0.6 to 1 microM. Proliferation was measured after 4 days using the ATP-chemosensitivity test. In MCF-7 cells 2ME in combination with 4OH-tamoxifen, epirubicine, docetaxel, 5-fluoprouracil, mafosfamide and carboplatin led to an additive effect. In BM cells only 2ME combined with 4OH-tamoxifen, daunorubicine and mafosfamide showed an additive action. Both letrozole and 2ME were nearly similar effective in inhibition of the aromatase gene. Here no additive effect was found. 2ME displayed antiproliferative actions in various human breast cancer cells. In addition 2ME was able to increase the antiproliferative property of certain antihormones and cytostatic substances. Furthermore 2ME exhibits a similar property as compared to letrozole in inhibiting the aromatase activity. Since 2ME was well tolerated in a recently conducted phase II trial in patients with refractory metastatic breast cancer, the combination of 2ME with chemotherapeutics or antihormones may offer a new clinically relevant treatment regimen.
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PMID:Chemotherapy of breast cancer-additive anticancerogenic effects by 2-methoxyestradiol? 1521 8

2-Methoxyestradiol (2-MeO-E(2)), a well-known nonpolar endogenous metabolite of 17beta-estradiol, has strong antiproliferative, apoptotic, and antiangiogenic actions in vitro and in vivo at pharmacologic concentrations. We determined in the present study whether 2-MeO-E(2) can enhance the anticancer actions of paclitaxel or vinorelbine (two commonly used microtubule-disrupting agents) in several human breast cancer cell lines, including the estrogen receptor-positive MCF-7 and T-47D cells and the receptor-negative MDA-MB-435s and MDA-MB-231 cells. 2-MeO-E(2) in combination with paclitaxel or vinorelbine exhibited a synergistic anticancer effect in these human breast cancer cells in vitro, and this synergistic effect was more pronounced when each of the drugs was used at relatively low concentrations. Additional experiments using female athymic BALB/c nu/nu mice showed that p.o. administration of 2-MeO-E(2) at 30 mg/kg body weight, once a week for 6 weeks, markedly enhanced the activity of paclitaxel or vinorelbine against the growth of the estrogen receptor-negative MDA-MB-231 human breast cancer xenografts in these animals. By contrast, combination of 2-MeO-E(2) with 5-fluorouracil only had a partial additive effect against the growth of these cell lines in culture, and no synergistic effect was observed. Interestingly, when doxorubicin was used in combination with 2-MeO-E(2), the antiproliferative effect of 2-MeO-E(2) was somewhat antagonized by doxorubicin when it was present at high concentrations. Our results showed that 2-MeO-E(2) at nontoxic or subtoxic doses selectively enhanced the effects of certain microtubule-disrupting agents (such as paclitaxel and vinorelbine) against the growth of the receptor-negative human breast cancer cells in culture and also in athymic nude mice.
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PMID:Synergism between the anticancer actions of 2-methoxyestradiol and microtubule-disrupting agents in human breast cancer. 1569 78

2-Methoxyestradiol (2-MeO-E2), a nonpolar endogenous metabolite of 17beta-estradiol, has strong antiproliferative, apoptotic, and antiangiogenic actions. Among the four human breast cancer cell lines tested (MCF-7, T-47D, ZR-75-1, and MDA-MB-435s), the ZR-75-1 cells were selectively insensitive to the antiproliferative actions of 2-MeO-E2, although these cells had a similar sensitivity as other cell lines to several other anticancer agents (5-fluorouracil, mitomycin C, doxorubicin, colchicine, vinorelbine, and paclitaxel). Mechanistically, this insensitivity is largely attributable to the presence of high levels of a steroid-selective metabolizing enzyme, the type II 17beta-hydroxysteroid dehydrogenase (17beta-HSD), in the ZR-75-1 cells, which rapidly converts 2-MeO-E2 to the inactive 2-methoxyestrone, but this enzyme does not metabolically inactivate other nonsteroidal anticancer agents. The type II 17beta-HSD-mediated conversion of 2-MeO-E2 to 2-methoxyestrone in ZR-75-1 cells followed the first-order kinetics, with a very short half-life (approximately 2 hours). In comparison, the T-47D, MCF-7, and MDA-MB-435s human breast cancer cells, which were highly sensitive to 2-MeO-E2, had very low or undetectable catalytic activity for the conversion of 2-MeO-E2 to 2-methoxyestrone. Reverse transcription-PCR analysis of the mRNA levels of three known oxidative 17beta-HSD isozymes (types II, IV, and VIII) revealed that only the type II isozyme was selectively expressed in the ZR-75-1 cells, whereas the other two isozymes were expressed in all four cell lines. Taken together, our results showed, for the first time, that the high levels of type II 17beta-HSD present in ZR-75-1 cells were largely responsible for the facile conversion of 2-MeO-E2 to 2-methoxyestrone and also for the selective insensitivity to the antiproliferative actions of 2-MeO-E2.
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PMID:Selective insensitivity of ZR-75-1 human breast cancer cells to 2-methoxyestradiol: evidence for type II 17beta-hydroxysteroid dehydrogenase as the underlying cause. 1599 56

2-Methoxyestradiol (2ME(2)), a metabolite of 17-beta-estradiol, inhibits angiogenesis and has additional antitumor activities. We have analyzed the tumor stage-specific effects of 2ME(2) in the C3(1)/Tag transgenic mouse model for breast cancer, which spontaneously develops estrogen receptor-negative mammary tumors following a predictable progression of lesion formation. When given either as a therapeutic agent in established tumors (late intervention study) or in mice with pre-invasive mammary lesions (early intervention study), tumor growth was reduced by 60% compared with untreated controls and was associated with an induction of apoptosis. In a prevention study, a significant reduction in mammary intraepithelial neoplasia (MIN) lesions was observed in animals beginning treatment at 6 weeks of age, before the appearance of histopathologic abnormalities. However, although 2ME(2) reduced the number of MIN lesions in the prevention study, a paradoxical increase in tumor multiplicity and growth rate was observed. This was associated with unusual cystic tumor formation, in which significant central necrosis was observed, surrounded by an outer region of proliferative tumor cell growth. The characteristics of the cystic tumor formation in mice treated with 2ME(2) at early ages are consistent with an impaired angiogenic response as observed in mice deficient for inhibitor of differentiation (Id-1). We further show that Id-1 expression is negatively regulated by 2ME(2), which may be an additional mechanism for the antiangiogenic effect of 2ME(2). Although 2ME(2) significantly reduced tumor growth at late stages, these results also suggest that altered tumor morphology and accelerated tumor growth may occur if 2ME(2) is administered in a prevention setting for prolonged periods.
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PMID:Distinct tumor stage-specific inhibitory effects of 2-methoxyestradiol in a breast cancer mouse model associated with Id-1 expression. 1658 73

2-Methoxyestradiol (2ME) is an estradiol metabolite with anti-tumor and anti-angiogenic properties. We studied the effect of 2ME on apoptosis of MCF-7 breast cancer cells and explored a combination therapy using 2ME and a polyamine analogue, bis(ethyl)norspermine (BE-3-3-3). Determination of viable cells on day 4 of treatment with 2ME/BE-3-3-3 combinations showed synergistic effects by Chou-Talalay analysis. APO-BRDU analysis showed that there was only 1.5+/-0.5% apoptosis at 200 nM 2ME and 3.7+/-1.7% in the presence of 2.5 microM BE-3-3-3. Combination of 200 nM 2ME and 2.5 microM BE-3-3-3 resulted in 52.2+/-2.6% apoptosis. Up to 90% of the cells underwent apoptosis in the presence of 1000 nM 2ME and 2.5 microM BE-3-3-3. Combination treatments resulted in total disruption of microtubules and depletion of putrescine, spermidine and spermine. In addition, phosphorylation of Akt and nuclear localization of cyclin D1 were altered by 2ME/BE-3-3-3 combination. Our results suggest an important strategy to induce apoptosis of breast cancer cells, with potential applications in therapy.
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PMID:Synergistic apoptosis of MCF-7 breast cancer cells by 2-methoxyestradiol and bis(ethyl)norspermine. 1718 9

Breast cancer is the leading cause of cancer deaths among women worldwide. The theory of targeting both cancer cells directly and their blood supply has significant therapeutic potential. However, to date, there are few clinically successful single agents that meet these criteria. 2-Methoxyestradiol-3,17-O,O-bis-sulfamate (2-MeOE2bisMATE) and 2-ethylestradiol-3,17-O,O-bis-sulfamate (2-EtE2bisMATE) are potent inhibitors of proliferation in a range of cancer cells. The work presented here demonstrates the potent in vitro and in vivo effects of these compounds. They cause apoptosis via the intrinsic mitochondrial pathway in both MDA-MB-231 breast cancer cells and endothelial cells. Furthermore, they are potent anti-angiogenic inhibitors in vivo, as shown by their ability to reduce endothelial staining in MDA-MB-231 xenograft tumors. We have developed a novel, flow cytometry based, ex vivo method which shows in cells recovered from MDA-MB-231 tumors treated with 2-MeOE2bisMATE and 2-EtE2bisMATE an increase in intra-tumoral G(2)-M arrest and apoptosis. The degree of apoptosis inversely correlates to tumor volume. Further in vivo studies reveal that both 2-MeOE2bisMATE and 2-EtE2bisMATE are orally bioavailable and extremely efficacious when compared to clinically tested drugs. As these compounds are anti-proliferative against breast cancer and endothelial cells they have the potential to be potent, dual acting clinical drugs of the future.
Breast Cancer Res Treat 2008 Sep
PMID:2-MeOE2bisMATE and 2-EtE2bisMATE induce cell cycle arrest and apoptosis in breast cancer xenografts as shown by a novel ex vivo technique. 1795 67


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