Journal Article•
A potent specific pure antiestrogen with clinical potential.
01 Aug 1991-Cancer Research (American Association for Cancer Research)-Vol. 51, Iss: 15, pp 3867-3873
TL;DR: The properties of ICI 182,780 identify this pure antiestrogen as a prime candidate with which to evaluate the potential therapeutic benefits of complete estrogen withdrawal in endocrine-responsive human breast cancer.
Abstract: Previous studies from this laboratory have described a series of 7 alpha-alkylamide analogues of estradiol with pure antiestrogenic activity, exemplified by ICI 164,384. A new compound, 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10 )- triene-3,17 beta-diol (ICI 182,780) has now been identified which has significantly increased antiestrogenic potency and retains pure estrogen antagonist activity. The antiuterotrophic potency of ICI 182,780 in the immature rat was more than 10-fold greater than that of ICI 164,384 (50% effective doses of 0.06 and 0.9 mg/kg, respectively). This order of magnitude increase of in vivo potency was also reflected, in part, by intrinsic activity at the estrogen receptor. The relative binding affinities of ICI 182,780 and ICI 164,384 were 0.89 and 0.19, respectively, compared with that of estradiol (1.0). Similarly, the in vitro growth-inhibitory potency of ICI 182,780 exceeded that of ICI 164,384 in MCF-7 human breast cancer cells, where 50% inhibitory concentrations of 0.29 and 1.3 nM, respectively, were recorded. ICI 182,780 was a more effective inhibitor of MCF-7 growth than 4'-hydroxytamoxifen, producing an 80% reduction of cell number under conditions where 4'-hydroxytamoxifen achieved a maximum of 50% inhibition. This increased efficacy was reflected by a greater reduction of the proportion of cells engaged in DNA synthesis in ICI 182,780-treated cell cultures compared with tamoxifen-treated cells. Sustained antiestrogenic effects, following a single parenteral dose of ICI 182,780 in oil suspension, were apparent in both rats and pigtail monkeys. In vivo, antitumor activity of ICI 182,780 was demonstrated with xenografts of MCF-7 and Br10 human breast cancers in nude mice. A single injection of ICI 182,780 provided antitumor efficacy equivalent to that of daily tamoxifen treatment for at least 4 weeks. The properties of ICI 182,780 identify this pure antiestrogen as a prime candidate with which to evaluate the potential therapeutic benefits of complete estrogen withdrawal in endocrine-responsive human breast cancer.
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TL;DR: The first installment of a reference collection of gene-expression profiles from cultured human cells treated with bioactive small molecules is created, and it is demonstrated that this “Connectivity Map” resource can be used to find connections among small molecules sharing a mechanism of action, chemicals and physiological processes, and diseases and drugs.
Abstract: To pursue a systematic approach to the discovery of functional connections among diseases, genetic perturbation, and drug action, we have created the first installment of a reference collection of gene-expression profiles from cultured human cells treated with bioactive small molecules, together with pattern-matching software to mine these data. We demonstrate that this "Connectivity Map" resource can be used to find connections among small molecules sharing a mechanism of action, chemicals and physiological processes, and diseases and drugs. These results indicate the feasibility of the approach and suggest the value of a large-scale community Connectivity Map project.
4,429 citations
TL;DR: Introduced to the Market in the Last Decade (2001−2011) Jiang Wang,† María Sańchez-Rosello,́‡,§ Jose ́ Luis Aceña, Carlos del Pozo,‡ and Hong Liu.
Abstract: Introduced to the Market in the Last Decade (2001−2011) Jiang Wang,† María Sańchez-Rosello,́‡,§ Jose ́ Luis Aceña, Carlos del Pozo,‡ Alexander E. Sorochinsky, Santos Fustero,*,‡,§ Vadim A. Soloshonok,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry, Faculty of Pharmacy, University of Valencia, Av. Vicente Andreś Estelleś, 46100 Burjassot, Valencia, Spain Laboratorio de Molećulas Orgańicas, Centro de Investigacioń Príncipe Felipe, C/ Eduardo Primo Yuf́era 3, 46012 Valencia, Spain Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastian, Spain IKERBASQUE, Basque Foundation for Science, Alameda Urquijo, 36-5 Plaza Bizkaia, 48011 Bilbao, Spain Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska Street 1, 02660 Kyiv-94, Ukraine
3,368 citations
TL;DR: It is postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.
Abstract: Preclinical strategies that are used to identify potential drug candidates include target-based screening, phenotypic screening, modification of natural substances and biologic-based approaches. To investigate whether some strategies have been more successful than others in the discovery of new drugs, we analysed the discovery strategies and the molecular mechanism of action (MMOA) for new molecular entities and new biologics that were approved by the US Food and Drug Administration between 1999 and 2008. Out of the 259 agents that were approved, 75 were first-in-class drugs with new MMOAs, and out of these, 50 (67%) were small molecules and 25 (33%) were biologics. The results also show that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches — with 28 and 17 of these drugs coming from the two approaches, respectively — in an era in which the major focus was on target-based approaches. We postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.
1,552 citations
TL;DR: The construction and characterization of a series of chimeric recombinases, each consisting of Cre fused to a mutated human oestrogen receptor (ER) ligand-binding domain (LBD) are reported, which should be useful for efficient spatio-temporally controlled site-directed somatic mutagenesis.
1,019 citations
TL;DR: It is demonstrated that the short-term effects of estrogen central to cardiovascular physiology are mediated by ERalpha functioning in a novel, nongenomic manner to activate eNOS via MAP kinase-dependent mechanisms.
Abstract: Estrogen is an important vasoprotective molecule that causes the rapid dilation of blood vessels by activating endothelial nitric oxide synthase (eNOS) through an unknown mechanism. In studies of intact ovine endothelial cells, 17beta-estradiol (E2) caused acute (five-minute) activation of eNOS that was unaffected by actinomycin D but was fully inhibited by concomitant acute treatment with specific estrogen receptor (ER) antagonists. Overexpression of the known transcription factor ERalpha led to marked enhancement of the acute response to E2, and this was blocked by ER antagonists, was specific to E2, and required the ERalpha hormone-binding domain. In addition, the acute response of eNOS to E2 was reconstituted in COS-7 cells cotransfected with wild-type ERalpha and eNOS, but not by transfection with eNOS alone. Furthermore, the inhibition of tyrosine kinases or mitogen-activated protein (MAP) kinase kinase prevented the activation of eNOS by E2, and E2 caused rapid ER-dependent activation of MAP kinase. These findings demonstrate that the short-term effects of estrogen central to cardiovascular physiology are mediated by ERalpha functioning in a novel, nongenomic manner to activate eNOS via MAP kinase-dependent mechanisms.
904 citations
Cites methods from "A potent specific pure antiestrogen..."
...The role of ER in the rapid response to E2 was determined during 15-min incubations done in the absence or presence of 10–8 M E2, with or without 10–6 M tamoxifen or 10–5 M ICI 182,780 added simultaneously (33)....
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References
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873 citations
"A potent specific pure antiestrogen..." refers background in this paper
...This diversity was first apparent in species differences of organ response (5) but re markably extends to differential effects of tamoxifen on estro gen-responsive genes within target cells (6)....
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TL;DR: Two separate radioimmunoassays for bovine and ovine luteinizing hormone (LH) have been developed and specificity of the assays was demonstrated by comparing radioimunnoassay and bioassay estimates of the LH content of pituitary preparations containing various ratios of the pituitARY hormones.
Abstract: Separate radioimmunoassays for bovine and ovine luteinizing hormone (LH) have been developed. Antiserum against LH was developed in rabbits and purified preparations of bovine and ovine LH were used for radioiodina-tion. Specificity of the assays was demonstrated by comparing radioimmunoassay and bioassay estimates of the LH content of pituitary preparations containing various ratios of the pituitary hormones. Using the bovine LH radioimmuno-assay and 200 μl aliquots of serum, relatively high levels (12–60 mg/ml) of LH were measured in serum from heifers on the day of estrus and measurable levels of LH were present in serum from castrated males (3–5 ng/ml). The ovine LH assay serum obtained from ewes on the day of estrus contained an average of 26 ng/ml, whereas serum obtained during the follicular and luteal phases of the cycle contained approximately 2 ng/ml. The average LH content of serum from castrated ewes was 4.9 ng/ml, whereas the level in castrated males was 20.9 ng/ml. Serum from normal male she...
852 citations
TL;DR: It is demonstrated that the agonistic effect of OHT on the whole hER is due to the cell‐type and promoter‐context dependent activity of TAF‐1, and it is confirmed that the wild type human oestrogen receptor has no ligand independent transcriptional activity.
Abstract: Various oestrogen responsive reporter genes and vectors expressing truncated or chimeric human oestrogen receptors (hER) containing either of the two independent hER transcriptional activation functions (TAF-1 and TAF-2) have been transfected into HeLa cells, chicken embryo fibroblast (CEF) or yeast cells to investigate the agonistic activity of the anti-oestrogen 4-hydroxytamoxifen (OHT). We demonstrate that the agonistic effect of OHT on the whole hER is due to the cell-type and promoter-context dependent activity of TAF-1. In similar experiments, we show that the anti-oestrogen, ICI 164,384, does not exhibit any oestrogenic activity and, therefore, acts always as a pure antagonist, even though it does not inhibit the activity of the isolated TAF-1. We also confirm that the wild type human oestrogen receptor has no ligand independent transcriptional activity. The implications of our results for the variable antagonist/agonist activity of anti-oestrogens in vivo are discussed.
773 citations
"A potent specific pure antiestrogen..." refers background in this paper
...The discovery of novel steroidal antiestrogens exemplified by ICI 164,384 (9, 10) provided for the first time pure estrogen antagonists which have shed new light on the physiology (11, 19-22) and the molecular mode of action of estrogens and antiestrogens (23-26)....
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Journal Article•
TL;DR: Development and growth of MCF-7 and ZR75-1 tumors in nude mice are estrogen dependent, and endocrine therapy by estrogen deprivation or antiestrogen treatment inhibits tumor cell proliferation in nude dogs, but does not cause tumor regression or loss of cell viability.
Abstract: Endocrine therapy with estrogen deprivation or with antiestrogens results in tumor regression in a subset of patients with advanced breast cancer. To better understand the mechanisms by which estrogens and antiestrogens modulate breast cancer growth in vivo, we have studied the effects of endocrine manipulation on the development and growth of tumors derived from cultured human breast cancer cells in the athymic nude mouse. MCF-7 breast cancer cells were inoculated into 6-week-old female BALB/c athymic nude mice. Tumor growth did not occur in ovariectomized mice. Cells remained viable, however, since estrogen supplementation more than 30 days later resulted in tumor formation. Minimal tumor growth was observed in intact female nude mice which have low circulating estrogen levels. Tumor development and growth in ovariectomized or intact mice supplemented with 17 beta-estradiol in the form of a s.c. pellet were dose dependent; growth rates increased with estrogen doses ranging from 0.01 to 0.5 mg. Antiestrogen treatment with either tamoxifen or LY156758 caused transient stimulation of tumor growth, followed by a prolonged stationary phase. Growth resumed with estrogen supplementation. Treatment of mice bearing established MCF-7 tumors with estrogen withdrawal (removal of estrogen pellet) resulted in cessation of tumor growth, but not in tumor regression. Growth inhibition was also observed with antiestrogens and was dose dependent. However, tumor regression did not occur, even in mice treated with high doses of tamoxifen (serum concentration of 1.0 microM) for as long as 60 days. Tumor growth was restored in these mice with estrogen replenishment. Tumor cells also remained viable histologically despite prolonged (1 month) estrogen deprivation or antiestrogen therapy, although the mitotic index was markedly reduced. Similar observations were made with mice inoculated with the hormone-responsive ZR75-1 human breast cancer cells, but not with hormone-independent MDA-231 cells which were not influenced by estrogen or antiestrogen treatment. In summary, development and growth of MCF-7 and ZR75-1 tumors in nude mice are estrogen dependent. Endocrine therapy by estrogen deprivation or antiestrogen treatment inhibits tumor cell proliferation in nude mice, but does not cause tumor regression or loss of cell viability.
443 citations
"A potent specific pure antiestrogen..." refers background or result in this paper
...The absence of superior efficacy of ICI 182,780, compared with that of tamoxifen, is consistent with the fact that tamoxifen lacks significant in vivo tumor growthstimulatory action, and high doses of tamoxifen did not cause tumor regression in short-term studies with this tumor model (34)....
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...Tumor growth ceased in ICI 182,780-treated animals but no significant tumor involution was seen, an effect consist ent with previous observations in this (33) and other (34) laboratories where estrogen withdrawal failed to precipitate tumor regression....
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Journal Article•
TL;DR: Tumors growing with TAM contained double the estrogen receptor content of the estradiol-stimulated MCF-7 tumors that were not exposed to TAM, which may represent a form of TAM resistance, i.e., TAM dependence that may occur before hormone independence is exhibited.
Abstract: Long-term tamoxifen (TAM) therapy was examined in athymic mice bearing MCF-7 tumors of different sizes. Six months of TAM treatment caused no increase in tumor size (compared to placebo treatment) for animals treated initially following implantation of tumor pieces (approximately 1 mm3) or for animals with 0.2-cm2 tumors (grown with 1 month of estrogen treatment). Tumors could be regrown with estradiol treatment in animals treated with either therapy and these tumors contained both estrogen and progesterone receptors. However, more tumors could be restimulated with estradiol following pretreatment with TAM than with placebo. A third group of animals had larger tumors (grown with 7 weeks of estrogen treatment to a approximately 0.6-cm2 area) before TAM or placebo treatment. These tumors partially regressed after 4 months of TAM or placebo therapy but began to regrow in both groups until the end of the experiment at 8 months. Tumors that grew in both groups were estrogen receptor positive and when retransplanted into athymic animals could grow with estradiol. However, the tumor that grew during TAM therapy, when retransplanted, could grow successfully only with further TAM treatment. Tumors growing with TAM contained double the estrogen receptor content of the estradiol-stimulated MCF-7 tumors that were not exposed to TAM [390 +/- 37 (SE) fmol/mg protein versus 174 +/- 14 fmol/mg protein]. These results may represent a form of TAM resistance, i.e., TAM dependence that may occur before hormone independence is exhibited.
440 citations
"A potent specific pure antiestrogen..." refers background in this paper
...In long-term exposure of MCF-7 xenografts tamoxifen-dependent tumors appear occasionally (37) and it has been shown that the continuing growth of such tumors can be blocked by concurrent administration of a pure antiestrogen (ICI 164,384; Ref....
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