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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antiestrogen therapy is the most widely used endocrine manipulation for the treatment of breast cancer, especially in postmenopausal women. Unfortunately, the compounds presently available possess mixed agonistic/antagonistic activity, thus potentially limiting their therapeutic efficacy. Following the observations that an aliphatic chain at the 7 alpha-position of 17 beta-estradiol does not prevent binding to the estrogen receptor while halogenation of estradiol can increase the affinity of its binding (expressed as RBA) to the estrogen receptor, we have synthesized a series of new steroidal antiestrogens (6-10) which possess both an 7 alpha-undecanamide group and an halogen atom (Cl, Br, or I) at the 16 alpha-position. The stereochemistry of these compounds was unambiguously established by high-field (400-MHz) nuclear magnetic resonance. Some of the compounds obtained possess potent in vivo antiestrogenic activity. At the low twice daily 3-micrograms dose, 16 alpha-chloro 3,17 beta-diol amide, 16 alpha-iodo 3,17 beta-diol amide, 16 alpha-bromo 3,17 beta-diol amide, 16 alpha-chloro 3,17 alpha-diol amide, and 16 alpha-bromo 3,17 alpha-diol amide inhibit by 74, 63, 52, 35, and 60%, respectively, the estradiol-induced stimulation of uterine weight in ovariectomized Balb/c mice while 78-99% blockade of estradiol action is achieved at the 20-micrograms dose. These new antiestrogens show no estrogenic activity on uterine weight at the doses used while tamoxifen (2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N- dimethylethanamine) shows full estrogenic activity and is only a weak partial antiestrogen in the same assay.
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PMID:Synthesis and biological activity of new halo-steroidal antiestrogens. 203 87

2-Phenylindole derivative 8, linked to aziridine by a hexamethylene spacer group, was synthesized and tested. It binds to the estrogen receptor with an RBA-value of 4.0 (estradiol = 100). In vitro, it shows a selective cytostatic activity in hormone-dependent MCF-7 breast cancer cells (41% T/C at 10(-6) M). In vivo, it exerts a strong estrogenic effect. The binding to the estrogen receptor is largely reversible.
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PMID:Synthesis and biological properties of a 1-(6-aziridinylhexyl)-2-phenylindole, a potential fluorescence label for estrogen receptors. 227 11

A number of acetoxy-substituted 5,6-dihydroindolo[2,1-a]isoquinolines were synthesized and tested for binding affinity for steroid hormone receptors. All of the derivatives bind to the estrogen receptor with RBA values ranging from 1.5 to 17 (17 beta-estradiol = 100). Some of them show binding affinities for the androgen receptor as well. In the mouse uterine weight test, the tetracycles proved to be weak estrogens with partial antagonistic activity. All of the compounds were tested in vitro for cytostatic activity with hormone-independent MDA-MB 231 and hormone-dependent MCF-7 breast cancer cells. A cytostatic effect was found in both cell lines. The comparison of results exhibited a stronger inhibitory effect on MCF-7 cells only for compounds with high binding affinity for the estrogen receptor. For those derivatives, it can be assumed that the growth inhibition is partly mediated by the estrogen receptor.
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PMID:Indolo[2,1-a]isoquinolines. Syntheses, steroid hormone receptor binding affinities, and cytostatic activity. 229 15

We have compared a new enzyme immunoassay for progesterone receptors (Abbott PgR-EIA, monoclonal) with our standard radioligand binding-assay (PgR-RBA). For both assays cytosols were freshly prepared from human breast cancer specimens that had been stored frozen for up to 1 year, and predominantly tissues were used which contained critically low amounts of progesterone receptors. A highly significant correlation was observed between the PgR-EIA and PgR-RBA (Spearman: Rs = 0.85, n = 100). Using a cut-off point of 10 fmol PgR/mg protein, 87% of the values were in accordance with each other (52% negative, and 35% positive in both assays), whereas 13% scored positive (median: 16, range 11-38 fmol PgR/mg protein) in one assay and negative (median: 7, range 0-10 fmol PgR/mg protein) in the other. Also in cytosols from human ovarian and endometrial carcinoma tissues immunoreactive PgR could be detected, and significant correlations with PgR-RBA were observed (Rs = 0.94, n = 6) for both tissues.
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PMID:Comparison of enzyme immunoassay and dextran-coated charcoal techniques for progesterone receptor determination in human breast cancer cytosols. 329 May 77

Hydroxy-2-phenylindoles carrying substituted benzyl groups and similar substituents at the nitrogen were synthesized and tested for their ability to displace estradiol from its receptor. All of the derivatives tested exhibited high binding affinities for the calf uterine estrogen receptor, with RBA values ranging from 0.55 to 16 (estradiol 100). The mouse uterine weight tested revealed only low estrogenicity for this class of compounds. Several derivatives showed antiestrogenic activity with a maximum inhibition of estrone-stimulated uterine growth of 40%. Two of the compounds (6c, 21c) were tested for antitumor activity in dimethylbenanthracene- (DMBA-) induced estrogen-dependent rat mammary tumors. Only the 4-cyanobenzyl derivative 21c was active. After 4 weeks of treatment with 12 mg/kg (6 times/week), the average tumor area was decreased by 57% (control +204%). In vitro, an inhibitory effect of 21b was only observed with hormone-sensitive MCF-7 breast cancer cells but not with hormone-independent MDA-MB 231 cells. These results make a mode of action involving the estrogen receptor system likely.
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PMID:2-Phenylindoles. Effect of N-benzylation on estrogen receptor affinity, estrogenic properties, and mammary tumor inhibiting activity. 380 90

The Mr 52,000 glycoprotein is regulated by estrogen and released by breast cancer cells in culture (B. Westley and H. Rochefort, Cell, 20: 352-362, 1980). This rare protein was partially purified from 25 liters of medium conditioned by MCF7 cells and injected into Biozzi's selected mice. The spleen lymphocytes of one immunized mouse was fused with the murine myeloma P3-X63-Ag8-653. Sixteen hybridomas producing monoclonal antibodies to the Mr 52,000 protein were isolated, and seven of them were cloned and purified. The seven monoclonal antibodies were all of the immunoglobulin G1 isotype, and their dissociation constants ranged from 0.35 to 2.3 nM. The antibodies specifically recognized the secreted Mr 52,000 protein as evidenced by double immunoprecipitation and by immunoblotting after electrophoretic separation and transfer. Double-determinant immunoradiometric assay indicated that the seven purified monoclonal antibodies recognized three distinct regions of the Mr 52,000 protein, and it was used to assay the Mr 52,000 protein in biological fluids. These antibodies did not react with the external plasma membrane of MCF7 cells, as shown by immunofluorescence analysis. By contrast, the cytoplasm of MCF7 cells (but not T47D and RBA cells) was stained by the peroxidase-immunoperoxidase complex after plasma membrane permeation, indicating that the protein is secreted by exocytosis rather than shed from the plasma membrane.
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PMID:Characterization of monoclonal antibodies to the estrogen-regulated Mr 52,000 glycoprotein and their use in MCF7 cells. 388 Nov 71

The antineoplastic activity of the antiestrogen 5-acetoxy-2-(4-acetoxyphenyl)-1-ethyl-3-methylindole (D 16726) was determined in several estrogen-dependent mammary tumor models. The growth of the DMBA-induced rat mammary carcinoma was inhibited by doses ranging from 1 to 12 mg/kg. The maximum decrease of tumor area was 67% (control + 635%). D 16726 was also active against MNU-induced rat mammary tumors and transplanted MXT tumors of the mouse. The growth of estrogen receptor-positive MCF-7 breast cancer cells was inhibited by the hydroxy derivative D 15414 (10(-8)-10(-5) M). Because of the high binding affinity of D 15414 for the estrogen receptor (RBA 6.7-10.0) and the lack of activity against hormone-independent MDA-MB 231 breast cancer cells, a specific mode of action involving the estrogen receptor is likely.
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PMID:The inhibitory effect of 5-acetoxy-2-(4-acetoxyphenyl)-1-ethyl-3-methylindole (D 16726) on estrogen-dependent mammary tumors. 392 26

Inhibitors of aromatase and 5 alpha-reductase may be of use for the therapy of postmenopausal breast cancer and benign prostatic hyperplasia, respectively. FCE 27993 is a novel steroidal irreversible aromatase inhibitor structurally related to exemestane (FCE 24304). The compound was found to be a very potent competitive inhibitor of human placental aromatase, with a Ki of 7.2 nM (4.3 nM for exemestane). In preincubation studies with placental aromatase FCE 27993, like exemestane, was found to cause time-dependent inhibition with a higher rate of inactivation (t1/2 4.5 vs 15.1 min) and a similar Ki(inact) (56 vs 66 nM). The compound was found to have a very low binding affinity to the androgen receptor (RBA 0.09% of dihydrotestosterone) and, in contrast to exemestane, no androgenic activity up to 100 mg/kg/day s.c. in immature castrated rats. Among a series of novel 4-azasteroids with fluoro-substituted-17 beta-amidic side chains, three compounds, namely FCE 28260, FCE 28175 and FCE 27837, were identified as potent in vitro and in vivo inhibitors of prostatic 5 alpha-reductase. Their IC50 values were found to be 16, 38 and 51 nM for the inhibition of the human enzyme, and 15, 20 and 60 nM for the inhibition of the rat enzyme, respectively. When given orally for 7 days in castrated and testosterone (Silastic implants) supplemented rats, the new compounds were very effective in reducing prostate growth. At a dose of 0.3 mg/kg/day inhibitions of 42, 36 and 41% were caused by FCE 28260, FCE 28175 and FCE 27837, respectively.
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PMID:Novel aromatase and 5 alpha-reductase inhibitors. 804 91

A number of methoxy-substituted 7,11b,12,13-tetrahydro-6H-dibenzo-[a,f]quinolizines with short alkyl groups in position 6 or 12 were synthesized by the Bischler-Napieralski reaction using the appropriate starting material followed by a second ring closure reaction involving a base-generated benzyne intermediate. The methoxy functions in positions 2 or 3 and 9 were cleaved with BBr3 and the free hydroxy groups converted into the acetates. The enantiomers of two of these derivatives were separated by liquid chromatography on triacetylcellulose. Compounds with alkyl substituents bind strongly to the estrogen receptor except those with a cis-orientation at the central ring connection. The RBA values ranged from 2.2-10.8 (17 beta-estradiol: RBA = 100). There was no major difference in binding between the (+) and (-)-enantiomers. The 3,9-diacetoxy-6-alkyl derivatives also showed binding affinity for the progesterone receptor (RBA: 1.2-3.1). The 2,9-diacetoxydibenzoquinolizines trans-61 and -6m with ethyl and propyl respectively in position 12 strongly inhibited the growth of hormone-sensitive MCF-7 breast cancer cells at concentrations of 10(-6) M and higher but were inactive in hormone-independent MDA-MB 231 breast cancer cells. Preliminary tests with hormone-dependent MXT mouse mammary tumors as model showed that these compounds have also antineoplastic activity in vivo. Derivative trans-61 at a dose of 20 mg/kg body weight, administered 3 times/week, inhibited the growth of these tumors by 78% (tamoxifen: 76% inhibition). Studies on the estrogenic and antiestrogenic properties of these agents in mice revealed that they are mixed agonists/antagonists with strong antiestrogenic activity at low doses but significant estrogenic effects at higher doses.
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PMID:Dibenzo[a,f]quinolizines: syntheses and cytostatic activity in estrogen-sensitive tumor cells. 814 64

In this study we prepared and evaluated a derivative of estradiol with an ethyl group at the 11 beta-position and an E-iodovinyl group at the 17 alpha-position. This new ligand binds to the estrogen receptor with an affinity slightly less than estradiol (RBA = 43%) at 0 degree C but much greater (RBA = 890%) at 25 degrees C. The 125I-labeled derivative was obtained by radioiododestannylation of the tri-n-butylstannyl precursor in good radiochemical yield with a specific activity exceeding 1500 Ci/mmol. The tissue distribution in immature female rats was evaluated over a 48 h period to determine uterine uptake and selectivity. Peak uterine uptake at 2 h was 6% ID/g and was significantly greater than that of [3H]estradiol, 2.4% ID/g. Substantial uptake in the uterus was still present at 48 h (2.4% ID/g). Co-administration of estradiol reduced the uptake at 2 and 24 h by 85%. Uterus-to-plasma ratios increased with time, from about 25:1 at 2 h to nearly 90:1 at 48 h. The affinity, ease of radiosynthesis and tissue distribution of the 17 alpha-E-[125I]iodovinyl-11 beta-ethyl-estradiol suggest that further evaluation of this agent as an imaging agent for estrogen-receptor-positive breast cancer is warranted.
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PMID:Synthesis, receptor binding and tissue distribution of 17 alpha-E[125I]iodovinyl-11 beta-ethyl-estradiol. 848 95


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