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)

1. Synergistic action of alpha-chlorohydrin with methallibure (ICI, 33828) on the testicular function of Presbytis entellus entellus Dufresne has been studied. 2. Chronic administration of alpha-chlorohydrin alone (140 mg/day for 40 days) caused testicular lesion resulting in a massive atrophy of the spermatogenic elements. Epididymal epithelium was regressed and the lumen was devoid of spermatozoa. 3. alpha-Chlorohydrin inhibited the synthesis of RNA and sialic acid in the testes and epididymides. Total cholesterol per gram of testis and alkaline phosphatase activity were increased after alpha-chlorohydrin administration. 4. These effects could be achieved with a lower dose of alpha-chlorohydrin (1/4) when administered in combination with a gonadotrophin inhibitor, i. e. ICI, 33828 (Methallibure). Methallibure alone (200 mg/kg: total dose) has no damaging effects on the testes and epididymides. But it altered testicular cholesterol and enzyme activity. 5. In conclusion, an effective inhibition of spermatogenesis could be achieved by synergistic action of the two different drugs i. e. alpha-chlorohydrin and ICI, 33828 (Methallibure).
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PMID:Chemical sterilization of male langurs: synergistic action of alpha-chlorohydrin (U-5897) with methallibure (ICI, 33828) on the testes and epididymides of Presbytis entellus entellus Dufresne. 41 Jun 36

Recent studies have demonstrated the presence of estrogen receptor (ER) in both normal human osteoblast-like and osteoblast-like osteosarcoma cells. The number of ER in cultured osteoblastic cells is very low (200-500 sites/cell). This has complicated characterization of the biological role of estrogens in bone cells. To study the responsiveness of bone cells to estrogens, we established osteoblast-like cell lines expressing higher ER levels. ROS 17/2.8, an osteoblastic cell line, was stably transfected with the cDNA encoding for the mouse ER. After a selection period, positive clones were isolated and evaluated for the presence of ER by both Northern blot analysis and ligand binding assays. Using these techniques, we detected a significant increase in the level of both ER transcript and binding compared to that in wild-type cells. The levels of expressed ER protein were similar to those reported in normal human osteoblast-like cells in primary culture (approximately 2000 sites/cell). To test whether the exogenously inserted ER was responsive, both wild-type and ER stably transfected cells were transiently transfected with a reporter construct containing an estrogen-responsive element linked to a truncated thymidine kinase promoter and a chloramphenicol acetyltransferase (CAT) reporter gene. Exposure of the cells to increased concentrations of estradiol induced a slight increase in CAT activity in wild-type cells (approximately 1.5-fold) at maximal stimulation; however, it provoked a clear concentration-dependent increase in CAT activity in the ER stably transfected cells, with a maximal stimulation of approximately 10-fold. This event was receptor mediated, since ICI 164,384, an ER antagonist, blocked the enhancement of estradiol-induced CAT activity, and it was specific, since other steroid hormones did not stimulate CAT activity. Finally, we evaluated the ability of ER to modulate an endogenous estrogen-responsive gene by measuring the activity of the enzyme alkaline phosphatase. In addition, diethylstilbestrol, a synthetic estrogen agonist, increased the activity of both the CAT reporter gene and the endogenous alkaline phosphatase enzyme. In summary, we have established osteoblast-like cells expressing high levels of an exogenously inserted ER, which has characteristics similar to those of the endogenous ER in terms of its Kd. Finally, the exogenous ER regulates both exogenously inserted construct (VITERECAT) and endogenous properties of the cells (enzymatic activity and proliferation).
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PMID:Estrogens modulate the responsiveness of osteoblast-like cells (ROS 17/2.8) stably transfected with estrogen receptor. 157 85

One hundred eighteen patients with stage D (D1 or D2) prostate cancer with a mean age of 69 years were treated with monthly goserelin (Zoladex; ICI 118, 630; ICI Americas Inc, Wilmington, DE, property of Imperial Chemical Industries PLC) injections and the data were analyzed for predictive parameters for best response and time to treatment failure (National Prostatic Cancer Project [NPCP] and Eastern Cooperative Oncology Group [ECOG] criteria). For best response in a univariate analysis, the performance status (PS 0-1 v 2-3) (P = .01), hematocrit (P = .04), and pain (P = .04) were significant. For time to treatment failure by univariate analysis, ECOG performance status (0-1 v 2-3) was most predictive (P less than .0001), followed by pain at entry (P = .0002), initial testosterone (T) level (greater than 250 ng/dL) (P = .0005), age less than 69 years (P = .02), alkaline phosphatase (less than 115 IU/L) (P = .03), hemoglobin (less than 14 g/dL) (P = .03), whereas normal acid phosphatase (less than 3 IU/mL) (P = .29) was not predictive. In multivariate analysis for time to treatment failure, only the ECOG performance status was of significance (P = .01). Estimated median time to treatment failure for PS of 0-1 was 88 weeks and for PS of 2-3 was 31 weeks.
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PMID:Predictive initial parameters for response of stage D prostate cancer to treatment with the luteinizing hormone-releasing hormone agonist goserelin. 213 2

A human endometrial tumor (Ishikawa) cell line in culture responded to estradiol stimulation, as measured by growth and alkaline phosphatase activity. These effects were similar whether the medium was enriched with serum or was serum-free. Estradiol increased placental alkaline phosphatase activity 2-3-fold over control in these Ishikawa cells. The mechanism for this increase appeared to be at the level of transcription, at least in part, since there was an increase in the concentration of placental alkaline phosphatase mRNA. The administration of tamoxifen or 4-hydroxytamoxifen was unable to antagonize the estradiol-stimulated alkaline phosphatase enzyme activity or mRNA expression. The administration of tamoxifen alone had no effect on alkaline phosphatase enzyme activity, but tamoxifen did stimulate the steady state concentration of alkaline phosphatase mRNA. In contrast, a new antiestrogen, ICI 164,384, was able to antagonize both of these estradiol-stimulated effects.
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PMID:Estrogen regulation of placental alkaline phosphatase gene expression in a human endometrial adenocarcinoma cell line. 233 23

A long-acting LRH agonist (ICI 118630, Zoladex) was given by monthly subcutaneous injection to 25 patients with previously untreated symptomatic advanced prostatic carcinoma. The medication was well tolerated with the only side effect being hot flushes in 15 patients. Subjective improvement occurred in 22 patients, and disease remission or stabilization judged by objective criteria was seen in 21 and 18 patients from the total group at 3 and 6 months of treatment, respectively. Twelve of 18 patients followed for 1 year were still in objective remission/stabilization. Prostate volume measured by ultrasound decreased by a mean value of 75% and urine flow increased significantly. There were significant falls in serum testosterone and gonadotrophin levels and significant although lesser reductions in serum androstenedione and dehydroepiandrosterone. These changes were accompanied by significant reductions in serum acid and alkaline phosphatase and a rise in serum osteocalcin. Four patients (16%) experienced an initial tumor flare. Although only a small number of patients were studied, Zoladex appeared to be a well-tolerated agent for treatment of prostatic carcinoma, with an initial clinical response similar to that seen with standard endocrine therapy.
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PMID:Treatment of metastatic prostate carcinoma with the depot LRH analog Zoladex. 296 31

The characteristics and localization of beta adrenoceptor subtypes in rat kidney sections have been examined using [125I]cyanopindolol and in vitro labeling combined with autoradiography. Binding was stereoselective since the (-)-isomers of propranolol and pindolol were some two orders of magnitude more effective as competitors than the (+)-isomers. Competition curves obtained using the subtype selective antagonists ICI 118,551 (beta-2) and betaxolol (beta-1) had low pseudo Hill coefficients and were resolved into two distinct components representing beta-1 (63%) and beta-2 adrenoceptors (37%). Combined autoradiographic and histochemical studies using nuclear emulsion-coated coverslips and alkaline phosphatase staining showed that the majority of receptors were in the renal cortex and in the outer band of the medulla with fewer receptors associated with the inner medulla, papilla and renal blood vessels. Delineation of beta-1 and beta-2 adrenoceptor subtypes with the selective antagonists betaxolol and ICI 118,551 indicated that the highly localized receptors were predominately of the beta-1 subtype, associated with glomeruli and with tubules that from their staining characteristics and topography represent distal and cortical collecting tubules with few if any receptors associated with proximal tubules. Beta-2 adrenoceptors were more diffusely distributed in the cortex and there were minor areas of localization in the inner medulla. Although some glomerular beta adrenoceptors probably play a role in control of renin release, their distribution throughout this structure indicates that they also control other functions. The distribution of beta adrenoceptors in tubules corresponds well with the known distribution of beta adrenoceptor-stimulated adenylate cyclase in rat kidney and indicates that these receptors subserve a physiological function.
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PMID:Localization of beta adrenoceptor subtypes in rat kidney by light microscopic autoradiography. 298 17

The quianazoline antifolate N10-propargyl-5,8-dideazafolic acid (ICI 155,387), an inhibitor of thymidylate synthetase (TS), was evaluated for clinical toxicity in a phase I trial. The compound was given once every week as a bolus injection. Fourteen patients with advanced cancer were treated at doses of 10-30 mg/m3. Four patients from the lowest to the highest dose developed severe renal toxicity, detected by a reversible decrease in the Cr-EDTA clearance. Hepatotoxicity was observed with transient elevations of alanine aminotransferase (ALT) in 10 patients and alkaline phosphatase in nine patients. Neither the incidence nor the severity of these toxicities was dose related. Two patients developed feelings of fatigue, which in one patient coincided with a decrease in Cr-EDTA clearance. No myelotoxicity, dermatological, gastrointestinal toxicity or mucositis was seen. No tumour responses due to ICI 155,387 occurred. The severity and the erratic nature of the renal side-effects suggest that this schedule cannot be recommended for further development of this compound in Phase II trials.
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PMID:A phase I evaluation of N10-propargyl-5,8-dideazafolic acid. 335 7

Some of the isoflavonoids present in human diet as well as in urine are expected to exert biologic effects as they have been reported to bind to estrogen receptors and to be estrogenic in other species. This report describes the in vitro assessment of estrogenic effects of isoflavonoids using human endometrial cells and tissue. The relative estrogenic potencies (EC50 values) of estradiol, 3 dietary isoflavonoids (coumestrol, genistein and daidzein) and one of their metabolites (equol), were estimated by using a recently developed multiwell plate in vitro bioassay based on the estrogen-specific enhancement of alkaline phosphatase (AlkP) activity in human endometrial adenocarcinoma cells of the Ishikawa-Var I line. The maximal AlkP activity elicited by the isoflavonoids tested was as high as that achieved with estradiol and their effects were suppressed by the antiestrogens 4-hydroxytamoxifen and ICI 164,384. These results indicate that estradiol and the isoflavonoids exert their effects on AlkP by similar interactions with the estrogen receptor, with potencies depending on binding affinities. The estrogenic effect of equol was confirmed by another in vitro bioassay, based on the estrogen-stimulated enhancement of prostaglandin F2 alpha output by fragments of human secretory endometrium.
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PMID:In vitro bioassays of non-steroidal phytoestrogens. 849 47

Osteoblasts are established targets of estrogen action in bone. We screened 66 conditionally immortalized clonal human osteoblast cell lines for estrogen receptors (ERs) using reverse transcriptase-polymerase chain reaction (RT-PCR) analysis for ER alpha mRNA and transactivation of adenovirus-estrogen response element (ERE)-tk-luciferase by 17 beta-estradiol (17 beta-E2) for functional ER protein. One of these cell lines, termed HOB-03-CE6, was chosen for further characterization. The cells, which were conditionally immortalized with a temperature-sensitive SV40 large T antigen, proliferated at the permissive temperature (34 degrees C) but stopped dividing at the nonpermissive temperature (> or = 39 degrees C). Alkaline phosphatase activity and osteocalcin secretion were upregulated by 1 alpha, 25-dihydroxyvitamin D3 in a dose-dependent manner. The cells also expressed type I collagen and other bone matrix proteins, secreted a variety of growth factors and cytokines, formed mineralized nodules based on alizarin red-S and von Kossa histochemical staining, and responded to dexamethasone, all-trans retinoic acid, and transforming growth factor-beta 1. This cell line expressed 42-fold less ER message than MCF-7 human breast cancer cells, as determined by quantitative RT-PCR. However, adenovirus-ERE-tk-luciferase activity was upregulated three- to fivefold in these cells by 17 beta-E2 with an EC50 of 64 pM. Furthermore, this upregulation was suppressed by co-treatment with the anti-estrogen ICI-182, 780. Cytosolic extracts of these cells specifically bound [125I]-17 beta-E2 in a concentration-dependent manner with a Bmax of 2.7 fmoles/mg protein (approximately 1,200 ERs/cell) and a Kd of 0.2 nM. DNA gel-shift analysis using a [32P]-ERE demonstrated the presence of ERs in nuclear extracts of these cells. Moreover, binding of the extracts to this ERE was blocked by a monoclonal antibody to the human ER DNA-binding domain. We evaluated these cells for 14 of 20 reported endogenous responses to 17 beta-E2 in osteoblasts. Although most of these responses appeared to be unaffected by the steroid, 17 beta-E2 suppressed parathyroid hormone-induced cAMP production, as well as basal interleukin-6 mRNA expression; conversely, the steroid upregulated the steady-state expression of alkaline phosphatase message in these cells. In summary, we have identified a clonal, conditionally phenotypic, human osteoblast cell line that expresses functional ERs and exhibits endogenous responses to 17 beta-E2. This cell line will be a valuable in vitro model for exploring some of the molecular mechanisms of estrogen action in bone.
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PMID:Functional properties of a conditionally phenotypic, estrogen-responsive, human osteoblast cell line. 913 93

Estrogen (E2) has been shown to prevent bone loss among postmenopausal women. The molecular mechanism(s) by which this is accomplished is not clear. The discovery of E2 receptor (ER) in osteoblasts and osteoclasts has implicated these cells as direct targets for E2. Previous studies on the effects of E2 on osteoblastic cells in vitro or in organ culture present conflicting results, possibly due to heterogeneity in cell types, stage of differentiation, ER levels, and/or species differences. The effects of E2 on gene expression during various stages of human osteoblast cell differentiation has not been investigated extensively. In this study we employed a newly developed human fetal osteoblastic cell line (hFOB/ER9) that contains high levels of ER to examine the effects of E2 on osteoblast proliferation and differentiation. The basal levels and E2 effects on the expression of various extracellular matrix proteins were also characterized throughout different stages of differentiation. These stages include a proliferative/relatively undifferentiated stage (day 6), a matrix maturation stage (days 10-14), and a mineralization/calcified nodule stage (day 18). During the stage of rapid cell proliferation, E2 treatment of hFOB/ER9 cells resulted in a dose-dependent decrease in [3H]thymidine incorporation to a maximum of 72% compared to the vehicle control value. Treatment of hFOB/ER9 cells with 10(-9) M E2 for 48 h resulted in an increase in alkaline phosphatase (AP) activity throughout cell differentiation. The magnitude of AP induction varied from approximately 200-500%. In contrast, E2 decreased osteocalcin protein levels to a minimum of 54% compared to the vehicle control value. The steady state messenger RNA levels for AP increased and osteocalcin decreased after E2 treatment, similar to the responses observed at the protein level. At all stages, there was little or no effect of E2 on type I collagen protein levels or osteonectin steady state messenger RNA levels. The E2 responses on hFOB/ER9 cell matrix protein expression and cell proliferation were mediated through the ER, as cultures cotreated with a 100-fold molar excess of a type II anti-E2 (ICI 182,780) abrogated these effects. These results support the hypothesis that E2 does have an effect on osteoblastic differentiation by decreasing hFOB/ER9 cell proliferation and differentially regulating extracellular matrix expression.
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PMID:Estrogen regulation of human osteoblastic cell proliferation and differentiation. 920 36


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