Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical study of compounds that modulate multidrug resistance in cancer cells has been hindered by both the toxicities of these agents and the inability to monitor their effectiveness at a cellular level. The non-steroidal triphenylethylene toremifene is well tolerated clinically and can sensitize multidrug resistant cells to the effects of doxorubicin in vitro. The chemosensitizing properties of toremifene in estrogen receptor negative, multidrug resistant MDA-A1 human breast cancer cells were studied using flow cytometric analysis. Cell cycle kinetics of MDA-A1 cells were not significantly affected by treatment with either toremifene or doxorubicin alone, as the majority of cells remained in G0/G1. However, preincubation with toremifene for 70 hours followed by treatment with doxorubicin caused a marked shift of cells to G2, as cells appeared to be blocked in that phase of the cell cycle. This result was nearly identical to the effect of doxorubicin alone on doxorubicin-sensitive MDA-MB-231 breast cancer cells and can be interpreted as a "resensitization" by toremifene of MDA-A1 cells to doxorubicin. This chemosensitizing effect of toremifene was accompanied by an enhanced accumulation of doxorubicin in MDA-A1 cells (+110% after 70 hours pre-incubation with toremifene), and by a depression in protein kinase C activity in MDA-A1 cells that was maximal following 70 hours incubation with toremifene. Flow cytometry is a widely available technique that might be applied clinically to monitor at the cellular level the chemosensitizing effects of toremifene and other modulators of multidrug resistance.
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PMID:Monitoring the chemosensitizing effects of toremifene with flow cytometry in estrogen receptor negative multidrug resistant human breast cancer cells. 146 71

The activity of sequentially administered hormonal therapy was investigated over 25 days in 25 patients with epithelial ovarian carcinoma who had estrogen receptor (ERc)-positive tumors. Patients received ethinyl estradiol (EE) (50 micrograms/d) on days 1 to 7 and medroxyprogesterone acetate (MPA) (400 mg/d) on days 8 to 25. Twenty-three patients completed one or more courses of treatment. There were no complete responses (CR). Four partial responses (PR) with durations of 9, 4, 3, and 1 months were seen. Two incomplete responses with durations of 6 and 4 months were also seen. Six patients had stable disease (SD), and 11 patients had progression. The overall response rate was 17% and may represent a modest improvement in response over those in previously published studies conducted with MPA alone. No significant toxic effects were noticed, and some patients reported an improved sense of well-being. However, two patients experienced depression with this treatment. The mean ERc values in responders, patients with SD, and nonresponders were 70.0, 36.7, and 47.9 fmol/mg cytosolic protein, respectively. Future studies of hormonal therapy in patients with ovarian carcinoma should attempt to identify more reliable indices for determining sensitivity to these agents.
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PMID:Sequentially administered ethinyl estradiol and medroxyprogesterone acetate in the treatment of refractory epithelial ovarian carcinoma in patients with positive estrogen receptors. 183 46

Previous studies have demonstrated an inverse relationship between estrogen receptor (ER) and epidermal growth factor receptor (EGF-R) gene expression in human breast cancer cells. This relationship was further investigated in MCF 7 cells treated with 12-O-tetradecanoylphorbol-13-acetate (TPA). Exposure to 10 nM TPA resulted in a time-dependent increase in EGF-R mRNA, first apparent at 3 h and maximal between 9 and 24 h. There was a concomitant fall in ER mRNA with a maximum decline to 15-20% of control between 12 and 24 h. Although EGF-R mRNA levels declined between 24 and 72 h, both EGF-R mRNA and EGF-R binding remained above control levels and this was accompanied by a sustained depression of ER mRNA. These data support the view that ER and EGR-R gene expression is inversely regulated in human breast cancer and describe for the first time an inhibitory effect of a phorbol ester on steroid hormone receptor gene expression.
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PMID:Modulation of estrogen receptor and epidermal growth factor receptor mRNAs by phorbol ester in MCF 7 breast cancer cells. 275 60

To inhibit endometrial stimulation during postmenopausal estrogen therapy, 25 women with climacteric symptoms were treated with a daily dose of 1.25 mg of conjugated estrogens for 7 weeks followed by a period of 10 days with clomiphene citrate administration (50 mg per day). This combination was repeated three times during the 6-month trial. The marked relief of climacteric symptoms with estrogen was slightly less during clomiphene treatment. Uterine bleeding occurred five times during estrogen treatment periods but never during or after clomiphene supplementation. Histologic examination revealed endometrial atrophy in 41% of the samples after the first estrogen treatment, whereas after the first and third clomiphene periods this was increased to 77% and 73%, respectively. The first clomiphene treatment significantly decreased the concentrations of cytosol estrogen and progestin receptors in endometrium, as compared with the levels recorded at the end of the preceding estrogen therapy. The depression in the cytosol estrogen receptor concentration was persistent, whereas cytosol progestin receptor concentration tended to increase during the subsequent estrogen-plus-clomiphene treatment. Estrogen declined serum concentration of follicle-stimulating hormone (FSH), whereas the concentration of luteinizing hormone (LH) and prolactin remained unchanged. Clomiphene did not change the levels of these hormones from those observed during the estrogen treatment. The concentration of free fatty acids in serum was increased during the estrogen and clomiphene treatments, whereas the levels of cholesterol and high-density lipoprotein--cholesterol did not change. Our results suggest that this treatment regimen relieves climacteric symptoms without endometrial stimulation or other adverse effects. Thus, clomiphene appears to be a practical alternative to progestin for interruption of the postmenopausal endometrial effect of estrogen.
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PMID:Postmenopausal hormone replacement therapy with estrogen periodically supplemented with antiestrogen. 626 54

High doses of estrogen (5-500 micrograms) induce regression of hormone-dependent DMBA mammary tumors in rats at the same rate and degree as treatment with the antiestrogen C1628 (Parke-Davis). In contrast, high dose estrogen stimulated growth of uteri in tumor-bearing rats, while C1628 was antiuterotrophic. Within 72 h following treatment with estrogen, diethylstilbestrol (DES), or C1628, changes in the levels of estrogen receptor (ER) and progesterone receptor (PgR) were evident in both uterine and mammary tumor tissue. Both estrogen and antiestrogen induced depression of the total cytosolic ER and altered the 8S/4S receptor ratio. The tumor cytosolic ER levels of DES- and C1628-treated rats were 4.67 +/- 1.7 fmol/mg protein and 15.89 +/- 3.1 fmol/mg protein, respectively, compared to 48.89 +/- 13.6 fmol/mg protein in tumors of untreated rats. In spite of reduced levels of cytosolic ER, there was an apparent increase in the 8S/4S ratio (62% increase in 8S/4S ER ratio compared to control 8S/4S ratio; p less than 0.05). Total uterine cytosolic ER was low after treatments with DES (5.69 +/- 2.08 fmol/mg protein) or C1628 (94.76 fmol/mg +/- 30.3 fmol/mg protein), as compared to untreated controls (188.2 +/- 7.6 fmol/mg protein). The cytosolic PgR was consistently high in tumors of control rats (42.99 +/- 11.9 fmol/mg protein) and in castrated rats treated with high doses of DES or C1628 (DES, 55.15 +/- 27.0; C1628, 65.07 +/- 9.8 protein).
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PMID:Effect of high-dose estrogen on growth and steroid receptor activity in DMBA-induced mammary tumors and uteri of rats. 634 12

The proportion of single intact viable mouse mammary tumor cells containing estrogen receptor (ER) as determined by 17-fluoresceinated estrone binding and the proportion labeled with [3H]thymidine (LI) have been assessed in the same cell population after either primary tumor removal, radiation, cyclophosphamide, or tamoxifen administration. Subsequent to tumor removal, the increase in LI occurring in a cell population from a residual tumor focus was associated with a concomitant decrease in the proportion of cells demonstrating 17-fluoresceinated estrone binding (fluorescence). As the level of LI in the tumor focus returned to that observed prior to tumor removal, the proportion of ER-containing cells simultaneously reverted to its original value. Following cyclophosphamide administration, there was a decrease in tumor LI and a concomitant elevation in the proportion of fluorescent cells which were dose related. The prolonged depression in LI following radiation was accompanied by a sustained increase in the proportion of ER-containing cells. Thus, the change in ER-containing cells was related to the alteration of the proliferating cell population by the various therapies. The findings support the thesis that fewer cells in the growth fraction of the tumor studied contain ER than in the nonproliferating cell pool. Following tamoxifen administration, a decrease occurred in the proportion of fluorescing cells due to competitive binding. There was no alteration in LI. This observation is not in conflict with the thesis that there is a correlation between ER and LI since the mechanism for reduction in detectable ER is different. These studies provide additional support to the credibility of the use of 17-fluoresceinated estrone binding for the determination of ER in individual tumor cells. They also indicate the usefulness of the method for obtaining biological information regarding tumor ER which cannot be obtained with the use of conventional biochemical analyses.
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PMID:Interrelation between tumor cell proliferation and 17-fluoresceinated estrone binding following primary tumor removal, radiation, cyclophosphamide, or tamoxifen. 661 61

16 alpha-[77Br]Bromoestradiol-17 beta (Compound 1) has been synthesized by radiobromination of estrone enoldiacetate. Tissue uptake studies performed 1 hr after administration of Compound 1 to immature or mature female rats showed uterus-to-blood ratios of 13, with nontarget issue-to-blood ratios ranging from 0.6 to 2. Co-administration of unlabelled estradiol caused a selective depression in the uterine uptake with no effect on nontarget tissue uptake. In adult animals bearing adenocarcinomas induced by DMBA (7,12-dimethylbenz(a)anthracene), tumor-to-blood ratios of 6.3 were obtained, this uptake also being depressed in animals treated with unlabeled estradiol. The studies demonstrate that Compound 1 has suitable binding properties and sufficiently high specific activity so that its uptake in estrogen target tissues in vivo is mediated primarily by the estrogen receptor. Furthermore, they suggest that this compound may be suitable for imaging human breast tumors that contain estrogen receptors.
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PMID:16 alpha-[77Br]bromoestradiol-17 beta: a high specific-activity, gamma-emitting tracer with uptake in rat uterus and uterus and induced mammary tumors. 677 76

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exhibits remarkably potent antiestrogenic activity. To further elucidate the role of estrogen receptor (ER) regulation in this response, we examined the effects of exposure to TCDD in MCF-7 human breast cancer cells on ER mRNA levels by using an RNase protection assay, on ER accumulation by using an ER immunocytochemical essay (ER-ICA), and on ER function by competitive binding assays under conditions of saturating 17 beta-estradiol (E2). Comparative studies were conducted with E2 and 12-O-tetradecanoylphorbol-13-acetate (TPA), as both compounds are known to suppress ER expression. Our results indicate that 1 nM E2 and 100 nM TPA both suppress ER mRNA levels as early as 4 h after exposure and to 33.6% and 16.5% of control levels, respectively, after 72 h. In contrast, no significant effect on ER mRNA levels was attributed to exposure to 10 nM TCDD. A greater than 50% reduction in positive staining was observed by ER-ICA after 72 h exposure to 1 nM E2 and to 100 nM TPA, while only an 11% reduction in positive staining was observed with 10 nM TCDD. Specific binding of [3H]E2 under saturating conditions (10 nM E2) in whole cells was reduced by 50% in cultures exposed to 100 nM TPA, although no effect on binding was observed with exposure to 10 nM TCDD. In contrast, specific binding using subsaturating 1 nM [3H]E2 was depressed by 49% in MCF-7 cells exposed to 10 nM TCDD for 72 h. This depression was inhibited by a 1-h treatment with 5 microM alpha-naphthoflavone, which inhibits TCDD-induced, P450-mediated, E2 metabolism, and subsequent E2 depletion. In conclusion, while TPA and E2 effectively down-regulate ER expression, TCDD, under antiestrogenic conditions, has little if any effect on total ER levels in MCF-7 cells, and thus ER modulation is probably not necessary for the suppression of estrogenic activity in MCF-7 cells by TCDD.
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PMID:Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin, 12-O-tetradecanoylphorbol-13-acetate and 17 beta-estradiol on estrogen receptor regulation in MCF-7 human breast cancer cells. 865 28

Tamoxifen is a synthetic antiestrogen with both agonist and antagonist properties. It is believed to act primarily through binding to estrogen receptors in breast cancer cells, acting as a competitive inhibitor of estrogen. Tamoxifen has a wide range of systemic effects, possibly acting on every estrogen target tissue in the body. Tamoxifen therapy is associated with a significant reduction in the risk of recurrence and death in postmenopausal women with early stage breast cancer. In addition, it has been shown to effectively suppress preclinical breast cancer, as evidenced by the decrease in second primary breast cancers in adjuvant trials. Tamoxifen is also the most widely used endocrine therapy for women with metastatic breast cancer. Tamoxifen, acting predominantly as an estrogen agonist in the liver, has generally favourable effects on serum lipids in postmenopausal women. In addition, tamoxifen has been shown to preserve bone mineral density and may even decrease the risk of osteoporosis in these women. Most patients treated with tamoxifen have minimal adverse effects. Vasomotor symptoms are the most commonly reported events. Less frequently, vaginal discharge or dryness, nausea and depression have been reported. A slight increase in thromboembolic events in postmenopausal women taking tamoxifen has been suggested in some adjuvant trials. Rarely, ocular toxicity and hepatotoxicity are found. The adverse effect of primary importance is the increased incidence of endometrial carcinoma. Several studies indicate that almost all of the tumours are of low histological grade and stage, similar to those seen with exogenous estrogen use. The relative risk of endometrial cancer in women taking tamoxifen is about 2 to 4 times higher than for postmenopausal women not taking tamoxifen. The benefits of tamoxifen outweigh the risks in almost all postmenopausal women with estrogen receptor-positive early stage breast cancer and in all women with metastatic breast cancer. Should tamoxifen prove to be an effective chemopreventive agent for breast cancer, the risks and benefits of treatment will have to be more carefully assessed for this setting.
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PMID:Tamoxifen in postmenopausal women a safety perspective. 893 95

Raloxifene hydrochloride (HCl) is a selective estrogen receptor modulator with estrogen agonist effects on bone and lipid metabolism and estrogen antagonist effects on reproductive tissues. Animal studies suggest that raloxifene may affect brain function as well, although the effects of raloxifene on the human brain remain to be established. This paper presents an early safety assessment of raloxifene effects on cognition and mood in postmenopausal women participating in a randomized, double-blind osteoporosis treatment trial. Psychometric test batteries were administered to postmenopausal women at baseline and 1, 6, and 12 months after initiating treatment with raloxifene (60 and 120 mg/day). The Memory Assessment Clinics (MAC) battery and Walter Reed Performance Assessment Battery (PAB) were used to assess multiple and independent aspects of cognitive function, while mood was assessed with the Geriatric Depression Scale (GDS). After 12 months of treatment, there were no significant differences between the raloxifene groups and placebo on performance in either the MAC battery or the PAB. The only significant difference observed was a slight increase in performance favoring the raloxifene 120 mg/day group in an assessment of verbal memory on the MAC battery after 1 month of treatment. Scores on the GDS and the self-reported incidence of mood-related events were not different between treatment groups at any of the assessment periods. These data do not suggest that raloxifene impairs cognition or affects mood in postmenopausal women treated for 1 year. Studies to further assess the safety and potential efficacy of raloxifene with respect to cognitive function are ongoing.
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PMID:Raloxifene hydrochloride, a selective estrogen receptor modulator: safety assessment of effects on cognitive function and mood in postmenopausal women. 1009 23


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