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)

Raloxifene is generally regarded as a tissue-selective estrogen agonist, being capable of selectively counter-acting both the loss of bone density and the increase in serum cholesterol that occur in rats following ovariectomy, without the induction of a trophic effect on the rat uterus. An implication of this activity profile is that reliance cannot be placed on the rat uterotrophic assay for the detection and assessment of xenobiotic estrogens. Within that context the estrogenic activity of raloxifene has been reevaluated in immature and ovariectomized rat uterotrophic assays. Four separate experiments were conducted. In the first two a reproducible increase (1.7-fold) was observed in the uterus wet weights of immature rats administered three daily doses of raloxifene. The maximum uterotrophic response observed over the dose range 0.01-2 mg/kg was for 0.1 mg/kg raloxifene. Further experiments utilized three daily doses of 0.1 mg/kg raloxifene. In the third experiment the uterotrophic response elicited by raloxifene in immature rats was abolished by coadministration of the estrogen receptor blocking agent Faslodex (ICI 182,780). This confirmed the direct involvement of estrogen receptors in the uterotrophic response elicited by raloxifene. Two further indications of the estrogenicity of raloxifene were obtained in this experiment. First, dry uterus weights were also shown to be increased by raloxifene administration, thereby eliminating water retention as the sole cause of the observed increases in uterus weights. Second, the height of the surface epithelium was increased by 1.7-fold in the raloxifene-treated animals, an effect that was accompanied by increases in mitotic activity and glandular formation in the stromal endometrium. The endometrial epithelium of the treated rats also showed evidence of vacuolation and, occasionally, the presence of degenerating cells. Raloxifene did not, however, cause premature vaginal opening in immature rats, unlike estradiol. In the fourth experiment the uterotrophic activity of raloxifene was confirmed in ovariectomized rats, although the response was less (1.2-fold) than in immature rats. In contrast to the effects seen for the positive control agent estradiol, the uterotrophic responses observed for raloxifene in ovariectomized animals were not accompanied by cornification of the vaginal epithelium. Premature vaginal opening and vaginal cornification may be less sensitive markers of estrogenic activity than the uterotrophic response. These collected observations confirm that raloxifene exerts a genuine trophic effect on the rat uterus, and as a consequence, the uterotrophic assay can be relied upon to detect estrogens with only a marginal effect on the uterus.
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PMID:Activity of raloxifene in immature and ovariectomized rat uterotrophic assays. 923 25

Tamoxifen is the endocrine therapy of choice for all stages of breast cancer. However, the drug cannot be considered to be a cure as drug resistance will eventually develop. The resistance can take two forms: either the loss of estrogen receptor or the selection of estrogen receptor positive disease that is tamoxifen stimulated for growth. Laboratory studies have demonstrated that tamoxifen-stimulated MCF-7 breast tumors can develop in athymic mice. A number of pure (nonestrogenic) antiestrogens have been discovered that can either be administered by injection (e.g., ICI 182,780) or orally (e.g., EM-800). In preliminary clinical studies, the compound ICI 182,780 (Faslodex) has been shown to be an effective second-line therapy after tamoxifen failure. The goal of future clinical studies is to evaluate the therapeutic efficacy and patient acceptability of aromatase inhibitors (postmenopausal estrogen withdrawal), and injectable or oral pure antiestrogens after the failure of long-term tamoxifen therapy. Clearly, the primary purpose for the treatment of advanced breast cancer is to control disease growth; nevertheless, an evaluation of the effect of new agents on bones and lipids is required before pure antiestrogens could be considered for adjuvant therapy.
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PMID:Pure antiestrogens as a new therapy for breast cancer. 943 92

Sex steroids accelerate bone maturation, but it is believed that estrogen action is needed for terminal epiphyseal fusion. In this study, we investigated the effects of a new estrogen-blocking agent, Faslodex (ICI 182,780), on estrogen-accelerated skeletal maturation in immature mice. On day-of-life 2 through 8, mice pups received either estradiol (5 microg/100 g body weight), Faslodex (100 microg/100 g body weight), a combination of Faslodex + estradiol, or vehicle alone. Skeletal maturation was assessed with a scoring system based on the size and appearance of epiphyseal plates in the forepaw and the lumbar spine. Estradiol caused acceleration of bone maturation in our mouse model (p < 0.05). Faslodex blocked the effect of estrogen, such that the mice receiving Faslodex + estradiol did not vary significantly from controls. Faslodex may prove useful in the treatment of patients with diseases causing rapid skeletal maturation, such as precocious puberty.
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PMID:The effects of the estrogen receptor blocker, Faslodex (ICI 182,780), on estrogen-accelerated bone maturation in mice. 1047 40

Androgens accelerate bone maturation, but it is unclear to what extent this process may be mediated by estrogens derived from aromatization of androgens. In this study, we investigated whether an estrogen-blocking agent, Faslodex (ICI 182,780), can attenuate testosterone-accelerated skeletal maturation in immature mice. On days of life 2-8, mouse pups received either testosterone propionate (50 microg/100 g body weight), Faslodex (100 microg/100 g body weight), a combination of Faslodex + testosterone, or vehicle alone. Skeletal maturation was assessed in the forepaw and the lumbar spine. Testosterone caused acceleration of bone maturation (p < 0.05, compared with vehicle), predominantly of axial bones. Faslodex, however, failed to block the effect of testosterone, such that the mice receiving Faslodex + testosterone had skeletal maturation scores similar to those treated with testosterone alone. These results suggest that androgens have the capacity to stimulate bone maturation directly, probably via their own receptors.
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PMID:Androgen-accelerated bone maturation in mice is not attenuated by Faslodex, an estrogen receptor blocker. 1133 22

This paper describes the establishment of an antiestrogen-resistant MCF7 breast cancer cell subline (FASMCF) by continuous culture of the estrogen-responsive parental line in steroid-depleted, ICI 182,780 (Faslodex; 10(-7) M)-supplemented medium. After a 3-month period of growth suppression, cells began to proliferate in ICI 182,780 at rates similar to those of untreated wild-type cells. Immunocytochemistry showed these cells to have reduced estrogen receptor and an absence of progesterone receptor proteins. RT-PCR and transient transfection studies with estrogen response element-reporter constructs confirmed that ICI 182,780-suppressed estrogen response element-mediated signaling. FASMCF cells show increased dependence upon epidermal growth factor receptor (EgfR)/mitogen-activated protein kinase (MAPK)-mediated signaling. Thus, EgfR protein and messenger RNA, growth responses to transforming growth factor-alpha, and extracellular signal-regulated kinase 1/2 MAPK activation levels are all increased. Unlike wild-type cells, FASMCF cells are highly sensitive to growth inhibition by an EgfR-specific tyrosine-kinase inhibitor (TKI), ZD1839 (Iressa), and an inhibitor of the activation of MEK1 (MAPKK), PD098059. Short-term ( approximately 3 weeks) withdrawal of cells from antiestrogen had no effect on growth or phenotype, whereas longer withdrawal (>10 weeks) appeared to partially reverse the cellular phenotype with increasing estrogen receptor and decreasing EgfR levels. In subsequent studies FASMCF cells were maintained in TKI, where their growth was again suppressed and secondary TKI resistance failed to develop within the 3-month period in which initial ICI 182,780 resistance arose. Furthermore, wild-type cells similarly maintained in combination ICI 182,780 and TKI treatment conditions remained growth arrested (>6 months), with notable cell loss through both reduced rates of cellular proliferation and increased cell death.
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PMID:Enhanced epidermal growth factor receptor signaling in MCF7 breast cancer cells after long-term culture in the presence of the pure antiestrogen ICI 182,780 (Faslodex). 1141 96

7Alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17beta-diol (ICI 182,780; Faslodex) is a novel steroidal antiestrogen. This partially blind, randomized, multicenter study compared the effects of single doses of long-acting ICI 182,780 with tamoxifen or placebo on estrogen receptor (ERalpha) and progesterone receptor (PgR) content, Ki67 proliferation-associated antigen labeling index (Ki67LI), and the apoptotic index in the primary breast tumors of postmenopausal women. Previously untreated patients (stages T(1)-T(3); ER-positive or -unknown) were randomized and received a single i.m. dose of ICI 182,780 50 mg (n = 39), ICI 182,780 125 mg (n = 38), or ICI 182,780 250 mg (n = 44) or oral tamoxifen 20 mg daily (n = 36) or matching tamoxifen placebo (n = 43) for 14-21 days before tumor resection surgery with curative intent. The ER and PgR H-scores, together with the Ki67LI were determined immunohistochemically in the matched pretreatment biopsy and the posttreatment surgical specimens. The apoptotic index was determined by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling on the same samples. The effects of treatment on each of these parameters were compared using analysis of covariance. ICI 182,780 produced dose-dependent reductions in ER and PgR H-scores and in the Ki67LI. The reductions in ER expression were statistically significant at all doses of ICI 182,780 compared with placebo (ICI 182,780 50 mg, P = 0.026; 125 mg, P = 0.006; 250 mg, P = 0.0001), and for ICI 182,780 250 mg compared with tamoxifen (P = 0.024). For PgR H-score, there were statistically significant reductions after treatment with ICI 182,780 125 mg (P = 0.003) and 250 mg (P = 0.0002) compared with placebo. In contrast, tamoxifen produced a significant increase in the PgR H-score relative to placebo, and consequently, all doses of ICI 182,780 produced PgR values that were significantly lower than those in the tamoxifen-treated group. All doses of ICI 182,780 significantly reduced Ki67LI values compared with placebo (ICI 182,780 50 mg, P = 0.046; 125 mg, P = 0.001; 250 mg, P = 0.0002), but there were no significant differences between any doses of ICI 182,780 and tamoxifen. ICI 182,780 did not alter the apoptotic index when compared with either placebo or tamoxifen. Short-term exposure to ICI 182,780 reduces the ERalpha in breast tumor cells in a dose-dependent manner by down-regulating ER protein concentration. The reductions in tumor PgR content by ICI 182,780 demonstrate that ICI 182,780, unlike tamoxifen, is devoid of estrogen-agonist activity. Reductions in tumor cell proliferative activity (as indicated by Ki67LI) show that ICI 182,780 is likely to have antitumor activity in the clinical setting.
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PMID:Comparison of the short-term biological effects of 7alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17beta-diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer. 1155 45

Tamoxifen is an effective treatment for breast cancer; however, as well as exerting antagonistic effects on the estrogen receptor (ER), tamoxifen acts as a partial agonists in estrogen-sensitive tissues, resulting in stimulation of the endometrium and tumor growth in some patients who become resistant to treatment.ICI 182, 780 (Faslodex), a steroidal estrogen antagonist, is the first in a new class of agent-an estrogen receptor downregulator. Pre-clinical breast cancer models show that ICI 182, 780 leads to a prolonged duration of response, and that it exerts its effects via a different mode of action to tamoxifen. This was confirmed in a small clinical study involving 19 post-menopausal advanced breast cancer patients, where ICI 182, 780 was highly effective after tamoxifen failure. Definitive evidence of the differing modes of action of ICI 182, 780 and tamoxifen, were provided in a study involving post-menopausal women with primary breast cancer, where analyses of tumor samples following short-term exposure to both drugs, showed that ICI 182, 780 reduced tumor ER levels in a dose-dependent manner, and to a significantly greater extent than tamoxifen. Additionally, unlike tamoxifen, ICI 182, 780 did not promote ER-mediated progesterone receptor expression, indicating that it lacks estrogen agonist activity. Ongoing studies in post-menopausal women with advanced breast cancer are comparing ICI 182, 780 to anastrozole and tamoxifen, respectively. Future studies being considered are whether ICI 182, 780 may also be effective in breast cancer in pre-menopausal women, in early breast cancer and in ductal carcinoma in situ in the breast, in combination with other hormonals, cytotoxics and biological modifiers.
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PMID:Faslodex (ICI 182, 780), a novel estrogen receptor downregulator--future possibilities in breast cancer. 1185 Feb 27

ICI 182,780 (Fulvestrant) is the first in a new class of novel, steroidal, 'pure' antioestrogens--the oestrogen receptor (ER) down-regulators. Its unique mode of action and the absence of partial agonist activity make it a candidate for the treatment of advanced breast cancer in both pre- and postmenopausal women. Tamoxifen has been available for use over the past 25 years. However, its partial agonist activity has been associated with detrimental effects, particularly on the endometrium, and may be associated with the development of tamoxifen resistance. Other antioestrogen agents have previously been unable to demonstrate clinically relevant activity following the development of resistance to tamoxifen. In contrast, the unique mechanism of action of ICI 182,780 results in significant clinical activity in patients failing on tamoxifen therapy. Indeed, phase III clinical trials have demonstrated that ICI 182,780 is at least as effective as the aromatase inhibitor anastrozole in the treatment of postmenopausal patients with advanced disease who have progressed during threatment with prior enocrine therapy. As such, ICI 182,780 will provide a valuable addition to the armamentarium for the treatment of advanced breast cancer.
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PMID:ICI 182,780 (Fulvestrant)--the first oestrogen receptor down-regulator--current clinical data. 1190 Feb 10

Systemic adjuvant therapy is recommended immediately following surgical removal of the primary tumour in the majority of patients with early breast cancer, to prevent the recurrence of distant metastases. Significant progress has been made in the development and evaluation of endocrine therapies for systemic adjuvant therapy. In pre- and perimenopausal women, ovarian ablation has proven to be a valuable treatment option, though not always desirable for young patients. Thus, reversible medical ovarian suppression with a luteinizing hormone releasing hormone agonist, such as goserelin (Zoladex), may provide an attractive alternative for such patients. International trials have indicated that goserelin provides an important addition to the choice of adjuvant therapies now available to pre- and perimenopausal patients. For postmenopausal patients, it is hoped that the ATAC (Arimidex, tamoxifen, alone or in combination) trial will reveal whether or not the benefits of anastrozole (Arimidex) observed in advanced disease, where it has proven to be well tolerated and at least as effective as tamoxifen in recent trials, will translate to the early setting to provide further management options for these patients. On the horizon is yet another exciting endocrine agent, ICI 182,780 (Fulvestrant), which has also been shown to be as effective as anastrozole in advanced disease. In terms of the future, these agents are likely to provide additional valuable treatment choices for early breast cancer across the patient spectrum.
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PMID:A vision for the future? 1190 Feb 11

Selective estrogen receptor modulators (SERMs) may act as estrogens or antiestrogens depending on the cell and tissue targets. The triphenylethylene SERMs are represented by tamoxifen and toremifene and a new agent with a novel carboxylic acid side chain (GW5638). Because of isomerization in the triphenylethylene molecule, "fixed ring" SERMs were introduced. The major one in development is the benzothiophene arzoxiphene (LY353381), which is now in Phase III clinical trial versus tamoxifen. A fourth group of SERMs is based on the estrogen molecule and comprises the so-called "pure" antiestrogen ICI 182,780 (fulvestrant, Faslodex) and a new oral analogue just entering trials, SR16234. The steroidal aromatase inhibitors [AIs (40H androstenedione 'and exemestane)] inactivate aromatase, whereas the triazole AIs (anastrozole and letrozole) inhibit the enzyme via the heme prosthetic group. Thus, there are two groups of AIs that show relative non-cross-resistance in advanced breast cancer and four groups of SERMs that also show a high degree of non-cross-resistance. With six different treatments and six or more clinical situations (prevention, neoadjuvant, adjuvant, and first- and second-line treatments for advanced disease) in which they may be used, the possible combinations of treatment are enormous. At present, we have few clinical pointers to optimal sequence of treatments. Now that most of the appropriate comparative trials have been performed, it may be the time to initiate novel approaches. These include alternating and sequential treatments, preferably with treatments changed before overt progression occurs.
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PMID:Future use of selective estrogen receptor modulators and aromatase inhibitors. 1191 32


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