Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00345 (ICI)
 5,388 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of human mammary tumour 800 x g supernatants with [3H]oestradiol after preincubation for 10 min at 0 degrees C with 10 mM dihydrolipoic acid resulted in metabolism of oestradiol. This was noted in 12 malignant tumours, 8 of which contained measurable oestrogen receptor levels. In 2 benign tumours lacking measurable levels of receptor, dihydrolipoic acid pretreatment had no effect. This metabolism was further stimulated by pretreatment with NAD, NADP and the anti-oestrogen Tamoxifen (ICI 46,474). When incubations were carried out in an O2 atmosphere using oxygenated buffers, the effect was suppressed.
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PMID:Metabolism of oestradiol by human mammary tumour 800 x g supernatants pretreated with dihydrolipoic acid. 4 33

The dose-related effects of non-steroidal antioestrogens and oestrogens on the measurement of cytoplasmic oestrogen receptors in the rat uterus have been determined. The simultaneous administration of tamoxifen or monohydroxytamoxifen and oestradiol on three consecutive days resulted in dose-dependent decreases in both the wet weight of the uterus and the number of available cytoplasmic oestrogen receptors. The oestrogenic triphenylethylenes ICI 47 699 and ICI 3188 both produced dose-dependent decreases in the number of available cytoplasmic oestrogen receptors. Increasing doses of ICI 47 699 resulted in increasing concentrations of oestrogen receptors within the nucleus. The effects of tamoxifen and oestradiol-17 beta were compared in the ovariectomized mouse; replenishment of uterine oestrogen receptors was less evident in tamoxifen-treated animals than in animals receiving oestradiol, although increases in uterine weight were similar. A single large dose of tamoxifen (50 microgram) produced a prolonged depletion of cytoplasmic oestrogen receptors whilst stimulating rises in uterine weight and DNA and protein content. The results demonstrate that the depletion of the uterine cytoplasmic oestrogen receptor pool is a function of the dose administered for any compound with the ability to translocate oestrogen receptors to the nucleus and as such is not an exclusive characteristic of non-steroidal antioestrogens.
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PMID:Dose-related effects of non-steroidal antioestrogens nad oestrogens on the measurement of cytoplasmic oestrogen receptors in the rat and mouse uterus. 68 74

Previous studies in this laboratory identified a series of 7 alpha-alkylamide analogues of 17 beta-oestradiol which are pure antioestrogens. Among this initial lead series of compounds, exemplified by ICI 164,384, none was of sufficient in vivo potency to merit serious consideration as a candidate for clinical evaluation. Further structure-activity studies identified a new compound, ICI 182,780, 7 alpha-[9-(4,4,5,5,5-pentafluoro-pentylsulphinyl)nonyl]oestra-1,3,5(10)- triene-3,17 beta-diol, with significantly increased antioestrogenic potency. The antiuterotrophic potency of ICI 182,780 is more than 10-fold greater than that of ICI 164,384. ICI 182,780 has no oestrogen-like trophic activity and, like ICI 164,384 is peripherally selective in its antioestrogenic effects. The increased in vivo potency of ICI 182,780 was also reflected, in part, by intrinsic activity at the oestrogen receptor and in the growth inhibitory potency of ICI 182,780 in MCF-7 human breast cancer cells. 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. Sustained antioestrogenic effects of ICI 182,780, following a single parenteral dose of ICI 182,780 in oil suspension, were apparent in both rats and pigtail monkeys. In vivo, the antitumour activity of ICI 182,780 was demonstrated with xenografts of MCF-7 and Br10 human breast cancers in athymic mice where, over a 1 month period, a single injection of ICI 182,780 in oil suspension achieved effects comparable with those of daily tamoxifen treatment. Thus, ICI 182,780 provides the opportunity to evaluate clinically the potential therapeutic benefits of complete blockade of oestrogen effects in endocrine-responsive human breast cancer.
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PMID:ICI 182,780, a new antioestrogen with clinical potential. 152 58

We have investigated the effects of ligand and DNA binding on the structure of the oestrogen receptor by performing limited proteolysis and analysing DNA binding activity by gel shift analysis. The effects of oestradiol, 4-hydroxytamoxifen and ICI 164,384 have been examined and we have found that despite differences in the DNA binding activity or relative mobility of the receptor-DNA complex we were unable to detect differences in the cleavage pattern produced by trypsin, chymotrypsin, Staphylococcus aureus V8, papain or elastase. Inhibition of DNA binding by ICI 164,384 was lost in receptor fragments that lacked the hormone binding domain. In contrast to the full-length receptor, proteolytic fragments produced by chymotrypsin differed in their ability to bind to an oestrogen response element (ERE) vs a thyroid response element (TRE). Evidence is presented that this difference can be accounted for by the inability of fragments lacking the hormone binding domain to dimerise on a TRE.
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PMID:Effect of ligand binding and DNA binding on the structure of the mouse oestrogen receptor. 156 7

Three monoclonal antibodies, H222, H226 and D547, which provided evidence of the structural transformation and change in exposure of the functional domains of the oestrogen receptor from fetal guinea-pig uterus upon activation, were used to study the receptor bound to the anti-oestrogens 4-hydroxytamoxifen and ICI 164,384. No differences in the structure of non-activated 4-hydroxytamoxifen- and ICI 164,384-receptor complexes, as compared with the oestradiol-receptor complex, were detected by the three monoclonal antibodies. When heated at 28 degrees C, both anti-oestrogen-receptor complexes became capable of binding the D547 antibody, which reacts selectively with the activated receptor; however, this binding was lower than that of the oestradiol-receptor complex. The interaction with the H226 antibody showed that anti-oestrogens can induce receptor dimerization, but to a lesser extent than oestradiol. In addition, both anti-oestrogen-receptor complexes can bind to DNA-cellulose and are retained in nuclei from intact cells at 28 degrees C, but less efficiently than the oestradiol-receptor complex. On the other hand, the nuclear receptor seems to have a similar dimeric structure when bound to either anti-oestrogens or oestradiol, as detected by the three monoclonal antibodies. The data suggest that 4-hydroxytamoxifen and ICI 164,384 induce and impaired activation of the oestrogen receptor; this difference, although quantitative rather than qualitative, might be related to the partial agonistic action of these anti-oestrogens in the fetal guinea-pig uterus.
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PMID:Studies on the activation of the oestrogen receptor bound to the anti-oestrogens 4-hydroxytamoxifen and ICI 164,384 by using three monoclonal antibodies. 189 45

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.
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PMID:Role of the two activating domains of the oestrogen receptor in the cell-type and promoter-context dependent agonistic activity of the anti-oestrogen 4-hydroxytamoxifen. 211 4

In premenopausal women with advanced breast cancer the luteinising hormone-releasing hormone agonist goserelin (Zoladex, ICI plc) will produce serum levels of oestradiol equivalent to those following surgical oophorectomy or the menopause. This paper reports our further experience of using this drug in 75 premenopausal patients with advanced breast cancer. In addition to response rates, duration of response is reported. An objective response was seen in 25 patients (33%), the median duration of which was in excess of 15 months. Seven patients (9%) showed a complete response to therapy; median duration greater than 37 months. There was no significant difference in time to disease progression (Lee-Desu statistic 18.26, 1 d.f., P = 0.43) and probability of survival (Lee-Desu statistic 3.41, 1 d.f., P = 0.07) between those patients assessed as having either static disease, or those showing a partial response at six months. Response to therapy correlates significantly with the oestrogen receptor status of the primary tumour (X2 = 20.59, 6 d.f., P less than 0.005). The modest side-effects, ease of administration and reversibility make this approach to therapy very attractive. This is to be remembered in that 53% of patients had disease progression whilst receiving goserelin. These patients thus avoided the unnecessary and irreversible morbidity associated with surgical oophorectomy. With the proven efficacy and minimal morbidity associated with goserelin we believe there is no current role for surgical oophorectomy in the management of premenopausal patients with advanced breast cancer.
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PMID:Goserelin (Zoladex) in premenopausal advanced breast cancer: duration of response and survival. 214 10

The kinetics of binding of oestradiol and the steroidal pure antioestrogen ICI 164,384 to the molybdate-stabilized oestrogen receptor, partially purified from pig and human uterine tissue, were determined. ICI 164,384 bound directly to the oestrogen receptor protein and the kinetic parameters of this interaction were, in general, similar to those for the binding of oestradiol, regardless of the source of the receptor protein. However, the rate of association of oestradiol, regardless of the source of the receptor protein. However, the rate of association of the antagonist with the receptor protein was slower when compared to that of oestradiol. Furthermore, the concentration of binding sites for the two ligands was of the same order. The binding of oestradiol resulted in a steroid-receptor complex which could be transformed in vitro, to a form with increased affinity for DNA-cellulose. However, the complex formed between ICI 164,384 and the receptor protein did not show increased affinity for DNA-cellulose when exposed to conditions that transformed agonist-receptor complexes. Therefore, the binding of ICI 164,384 to the oestrogen receptor protein results in a suppression of the transformation process. A similar suppression in vivo may account for the pure antagonist properties of ICI 164,384.
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PMID:A comparative study of the interaction of oestradiol and the steroidal pure antioestrogen, ICI 164,384, with the molybdate-stabilized oestrogen receptor. 232 8

ICI 164,384 is a novel agent, which has all the characteristics of a pure anti-oestrogen in preclinical studies. It completely inhibited oestradiol or tamoxifen-induced uterine growth in immature rats. In intact rats, ICI 164,384 produced a reduction in uterine weight, almost equivalent to that in ovariectomised rats. ICI 164,384 also demonstrated a peripherally selective action in intact rats. ICI 164,384 has a high affinity for the oestrogen receptor and was more effective than tamoxifen in blocking proliferation of MCF-7 human breast cancer cells. Extrapolation of these observations to the therapy of breast cancer would imply that a pure anti-oestrogen might provide additional benefit, compared with Nolvadex, in terms of onset, duration or completeness of response.
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PMID:The potential for a novel pure anti-oestrogen. 261 11

The effects of ICI 164,384 on the expression of six oestrogen-regulated RNAs (pNR-1, pNR-2, pNR-13, pNR-17, pNR-25 and pNR-100) and the 46 kDa secreted protein were measured in MCF-7 cells. In marked contrast to tamoxifen, an antioestrogen commonly used in the treatment of breast cancer, ICI 164,384 administered alone had little or no effect on the RNAs or protein. ICI 164,384 completely inhibited the induction of the RNAs and 46 kDa protein by oestradiol. Although ICI 164,384 has an affinity for the human oestrogen receptor only slightly less than that of oestradiol, half maximal inhibition of oestradiol action was attained with between a 50 and 150-fold molar excess of ICI 164,384. The pNR-1 RNA is induced by tamoxifen but this induction was abolished by ICI 164,384. Thus, ICI 164,384 acts as a potent antioestrogen for the regulation of the expression of specific oestrogen-responsive genes in human breast cancer cells.
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PMID:Effects of the antioestrogen, ICI 164,384, on oestrogen induced RNAs in MCF-7 cells. 276 Dec 57


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