Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This updated literature review on heterosteroids and drug research has information on chemical structure, pharmacology, and effects. It first discusses the anti-inflammatory heterosteroids, such as mometasone furoate and cortivazol. It also covers heterosteroidal antimineralocorticoids and anabolic hetero derivatives. The review discusses at length the 19-norsteroid, mifepristone (RU-486), which exhibits antiprogestational activity and is being used for fertility control in women. It also has antiglucocorticoid activity and shows promise as a treatment of diseases characterized by muscle atrophy. In vitro studies indicate that mifepristone inhibits growth of breast cancer cell lines and of endometrial cancer cell lines. It has already exhibited growth inhibitory effects in some breast cancer patients. Discussions of mifepristone's pharmacokinetics and structural modifications of mifepristone follow. Danazol is an antigonadotropin and is used to treat endometriosis, benign breast disease, precocious puberty, hereditary angioneurotic edema, menorrhagia, some types of infertility, and gynecomastia. Danazol effects considerable changes in lipid metabolism. Other hormonal, antihormonal, and/or antifertility heterosteroids and/or aspects include androgen antagonists (e.g., cyproterone acetate), estrogen activity, antiestrogens, STS-557, and oximinosteroids. Heterosteroidal inhibitors of steroid hormone biosynthesis discussed are aromatase inhibitors, 5 alpha-reductase inhibitors, and 3 beta-hydroxysteroid dehydrogenase inhibitors (trilostane, epostane, and azastene). Heterosteroids affect the cardiovascular system, including the cardiac glycosides, antiarrhythmic agents, and antilipemic agents. Some heterosteroids affect central nervous system activity (e.g., RU-5135 causes convulsions in rodents). Pancuronium analogues and chandonium and analogues are neuromuscular blocking azasteroids. In addition to danazol and RU-486, several other antineoplastic heterosteroids exist (e.g., estramustine phosphate sodium, a prostate cancer drug).
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PMID:Heterosteroids and drug research. 184 48

Inhibitors of aromatase, the cytochrome P-450 enzyme complex responsible for the biosynthesis of estrogens, may be useful as therapeutic agents for the treatment of estrogen-dependent disease states such as breast and endometrial cancer. Several 7 alpha-thio-substituted androstenediones have proven to be potent inhibitors of aromatase in vitro and in vivo. Recent research efforts have focused on designing aromatase inhibitors with both substitution at C-7 and extended linear conjugation in rings A and B of the steroid nucleus. The targeted compounds, 7-substituted 4,6-androstadiene-3,17-diones 4-10, were prepared by the addition of either Grignard or lithium reagents to 3,3:17,17-bis(ethylenedioxy)-5-androsten-7-one (3). Inhibitory activities of the compounds were evaluated in vitro by enzyme kinetic studies employing the microsomal fraction isolated from human term placenta. 7-Benzyl- and 7-phenethyl-4,6-androstadiene-3,17-dione analogues are effective inhibitors with apparent Ki's of 60.9-174 nM, while the 7-phenyl analogue exhibited an apparent Ki of 1.424 microM. Thus, several 7-substituted 4,6-androstadiene-3,17-diones were prepared and exhibited good competitive inhibition of aromatase in vitro in human placental microsomes.
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PMID:Synthesis and biochemical studies of 7-substituted 4,6-androstadiene-3,17-diones as aromatase inhibitors. 229 6

Estrogen biosynthesis (aromatase activity) was investigated in human adenomyosis tissue and compared with that of the normal myometrium, endometrium, and endometrial cancer tissues. Homogenates were incubated with [1,2,6,7-3H]androstenedione and NADPH at 37 degrees C for 1 h. After stopping the enzymatic reaction with ethyl acetate, [4-14C]estrone and [4-14C]estradiol-17 beta were added to the incubated sample. Estrone and estradiol were purified and identified by Bio-Rad AG1-X2 column chromatography, thin-layer chromatography and co-crystallization. Estrogen formed in the incubated sample was calculated from the 3H/14C ratio of the final crystal. The value for estrone formed from androstenedione was 52-132 fmol.h-1.g-1 wet weight. Aromatase activity in the adenomyosis tissues was higher than that in normal endometrial or myometrial tissues, but lower than that found in myometrial or endometrial tumour tissue. Furthermore, we investigated the effect of danazol, progesterone, and medroxyprogesterone acetate on adenomyosis cells in primary cultures. Aromatase activity in adenomyosis was blocked by danazol, but stimulated by progesterone and MPA. These results indicate that aromatase activity in adenomyosis may contribute to the growth of the ectopic endometrial tissue which occurs in this disease.
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PMID:Estrogen biosynthesis in human uterine adenomyosis. 252 61

Inhibitors of aromatase, the cytochrome P-450 enzyme complex responsible for the biosynthesis of estrogens, may be useful therapeutic agents for the treatment of estrogen-dependent disease states such as breast and endometrial cancer. 7 alpha-Substitution of androstenedione results in inhibitors of enhanced affinity for aromatase, with 7 alpha-(4'-amino)phenylthio-4-androstene-3,17-dione (7 alpha-APTA) exhibiting an apparent Ki of 18 nM and being among the most potent competitive inhibitors produced. The effects of this potent competitive 7 alpha-substituted C19 aromatase inhibitor on reduction of the number and size of the 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats was investigated. Tumor-bearing rats receiving 25 or 50 mg 7 alpha-APTA/kg/day demonstrated reductions in tumor volumes during the first week. Tumor volumes continued to decrease during the studies, resulting in tumor volume reductions of approximately 40 and 80%, respectively. Tumors in rats of the control group receiving only vehicle steadily increased in size during the studies. The tumor reductions in a 50-mg/kg/day-treated group were reversed by coadministration of 7 alpha-APTA at 50 mg/kg/day and estradiol at 0.3 microgram/kg/day for the last 3 weeks, indicating that the tumors were still responsive to estrogen. Plasma levels of estradiol were lower in the animals treated with 7 alpha-APTA at the end of the treatments. Thus, 7 alpha-APTA is effective in reducing tumor volumes in the estrogen-dependent 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma rat model. These results encourage further development of these steroids as potential medicinal agents for the treatment of estrogen-dependent disease states such as breast and endometrial cancer.
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PMID:Effects of the aromatase inhibitor 7 alpha-(4'-amino)phenylthio-4-androstene-3,17-dione on 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats. 314 Oct 48

Enzyme-activated inhibitors of aromatase would result in effective medicinal agents for modulating estrogen-dependent processes and thus may be useful in controlling reproductive processes and in treating estrogen-dependent diseases such as breast and endometrial cancer. A potential enzyme-activated inhibitor of aromatase, 7 alpha-(4'-amino)phenylthio-1,4-androstadiene-3,17-dione (7 alpha-APTADD), was synthesized and examined in vitro with placental aromatase. Under initial velocity conditions, 7 alpha-APTADD exhibited high affinity for the enzyme and is a potent inhibitor of aromatase with an apparent Ki of 9.9 +/- 1.0 nM and with a Km for androstenedione of 52.5 +/- 5.9 nM. This inhibitor produced a rapid time-dependent, first-order inactivation of aromatase in the presence of NADPH, while no inactivation of aromatase activity was observed in the absence of NADPH. Protection of aromatase from inactivation was observed when the substrate, androstenedione, was included in the incubation mixture containing enzyme, inhibitor, and NADPH. On the other hand, nucleophilic trapping agents such as cysteine did not protect the enzyme from inactivation by 7 alpha-APTADD. Additionally, second enzyme pulse experiments demonstrated identical rates of inactivation, suggesting that the enzyme-activated inhibitor was not being released from the active site of the enzyme. The apparent Kinact for 7 alpha-APTADD is 159 +/- 21 nM and represents the inhibitor concentration required to produce a half-maximal rate of inactivation. The half-time of inactivation at infinite inhibitor concentration was 1.38 +/- 0.92 min and is the most rapid enzyme-activated aromatase inhibitor reported to date. Thus, 7 alpha-APTADD is a potent enzyme-activated inhibitor of aromatase, exhibiting high affinity and rapid inactivation. This inhibitor will be useful in probing the biochemistry of aromatase and should also serve as an effective medicinal agent for the treatment of estrogen-dependent cancers.
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PMID:Potent enzyme-activated inhibition of aromatase by a 7 alpha-substituted C19 steroid. 359 93

Aromatase activity and concentrations of cortisol, progesterone and testosterone were measured in samples of breast and abdominal adipose tissue obtained from both pre- and postmenopausal subjects. Enzyme activity was determined by the incorporation of tritium from [1 beta-3H]androstenedione into water and found to be in close agreement to that measured when tritium labelled oestrone (E1) and oestradiol (E2) were isolated. No significant difference in enzyme activity was noted between breast and abdominal adipose tissue. Increased aromatase activity was not observed in adipose tissue taken from a subject with endometrial cancer. Cortisol concentrations were found to be significantly higher (P less than 0.05) in abdominal as compared to breast tissue. Without attaining statistical significance progesterone concentrations were higher in abdominal as compared to breast adipose tissue. Aromatase activity was not related to either cortisol or testosterone tissue concentration, but an inverse relationship between progesterone concentration and aromatase activity was observed (r = 0.542, P less than 0.02). On the basis of results obtained a hypothesis for the increased conversion of androgen to oestrogen as seen after the menopause has been proposed.
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PMID:Aromatase activity and concentrations of cortisol, progesterone and testosterone in breast and abdominal adipose tissue. 372 41

Adipose tissue is the principal site of extraglandular estrogen formation in nonpregnant women. The importance of adipose tissue as a site of estrogen formation is emphasized by the finding that increased body weight is associated with an increased incidence of endometrial carcinoma. In the present study, the kinetics of estrogen formation from androstenedione by adipocytes and by stromal cells isolated from human adipose tissue as well as by membrane fractions prepared from these cells were investigated. Subcutaneous adipose tissue samples obtained from women were dispersed by collagenase treatment, and aromatase activity was assayed by the incorporation of tritium from [1-3H]androstenedione into [3H]water. As previously reported, aromatase activity was found in intact stromal cells of adipose tissue, whereas little aromatase activity was detected in intact adipocytes. When crude membrane fractions (100,000 X g pellet) of stromal cells and adipocytes were incubated in the presence of [1-3H]androstenedione and an NADPH-generating system, however, aromatase activity was found in membrane fractions of both stromal cells and adipocytes, and estrogen formation increased in a linear manner as a function of time and membrane protein concentration. The apparent Michaelis constant (Km) of aromatase for androstenedione of intact stromal cells was 0.03 microM, whereas intact adipocytes did not convert androstenedione to estrone at substrate concentrations up to 3.0 microM. In membrane fractions of stromal cells, the rate of aromatization as a function of androstenedione concentration did not follow simple Michaelis-Menten kinetics, and both low affinity (Km = 1.03 microM) and high affinity (Km = 0.10 microM) components were observed. The affinity of androstenedione for aromatase of adipocyte membrane fractions was low; the rate of aromatization was not saturable at concentrations of androstenedione up to 3.0 microM. When intact adipocytes were incubated with [1-3H]androstenedione, then homogenized, and the homogenate was treated by differential centrifugation, the radioactivity that was added to the medium was found almost entirely in the lipid fraction of the cells. This finding is indicative that the low aromatase activity in intact adipocytes is the result of sequestration of steroid in lipid droplets in the cells. We suggest that the stromal cells of adipose tissue are a major source of the increased estrogen production in obese persons; a role for adipocytes in the regulation of adipose tissue estrogen formation, however, cannot be excluded at this time.
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PMID:Aromatase activity of membrane fractions of human adipose tissue stromal cells and adipocytes. 664 29

The ability of human endometrium to synthesize estrogen from testosterone (T) was investigated. Normal and malignant endometrial specimens were incubated in a complete nutrient medium with 1 muC/ml (approximately 10 pmol/ml) of [3H]T for 20 hrs. Various estrogens: estrone (E1), estradiol (E2), estrone sulfate (E1S), and estradiol-3-sulfate (E2S) were isolated from cultured tissue and medium. The capacity of aromatization, expressed in pmol of estrogen formed/g of tissue, of proliferative endometria was found to be significantly higher than that of secretory endometria (prol. n=12, 0.53 +/- 0.21, vs sec. n=13, 0.15 +/- 0.09, mean +/- s.d., P less than 0.005). In nine cancer endometrial specimens studied, the estrogen produced varied from 0.3 to 15 pmol/g of tissue. These studies represent the first evidence that human endometrium is capable of synthesizing estrogens from delta 4 androgens at a concentration similar to plasma level. The changes of the capacity of aromatization during the two phases of the menstrual cycle indicate that the estrogen synthesis in endometrium is apparently regulated by hormones. The presence of aromatase in cancer endometria may play an important role in promoting the cell growth in estrogen sensitive endometrial cancer.
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PMID:Estrogen synthesis in normal and malignant human endometrium. 711 84

Estrogen receptors of human endometrial cancer Ishikawa cells were found to be present in moderate amounts (160-200 fmol/mg protein), and to specifically bind moxestrol (R2858) with a very high affinity characterized by a Kd around 60 pM, when measured under equilibrium conditions. The binding specificity respected a decreasing order as follows: estradiol (E2: 100%) > 4-hydroxy-tamoxifen (4OHTAM: 52.7%) > estriol (E3: 5.7%) > estrone (E1: 2.1%) > TAM (0.2%). The induction of alkaline phosphatase activity (APase) used as an estrogen-specific response, confirmed the intrinsic estrogenicity of progestins derived from 19-nor-testosterone (19NT): norethindrone (NOR), norethynodrel and levonorgestrel, at concentrations ranging from 10(-8) to 10(-6) M. The effect of NOR was partially blocked by the antiestrogen 4OHTAM, which was also partially agonistic in this model, but neither by the antiprogestin mifepristone (RU486) nor by the aromatase inhibitor aminoglutethimide. A simulatory effect was also detected at 10(-7) or 10(-6) M with ethindrone, the testosterone- (T) derived progestin homologous to NOR, and with both androgenic parent-compounds, i.e. T and 19NT themselves. In contrast, progesterone (P) derivatives like medroxyprogesterone acetate (MPA) and chlormadinone acetate (CMA) remained totally inactive, as well as 19-nor-progesterone (19NP) itself or its progestagenic derivatives: ORG 2058 and nomegestrol acetate (NOM). Structure-activity relationships deduced from these studies suggest that it is not the absence of the 19-methyl group which can account for the estrogenic potential of the so-called "19-norprogestins", but rather their steroid structure derived from T in a broad sense (including the 19NT derivatives), as opposed to the non-estrogenic therapeutic progestins derived from P like MPA or CMA, or from 19NP like NOM.
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PMID:Lack of estrogenic potential of progesterone- or 19-nor-progesterone-derived progestins as opposed to testosterone or 19-nor-testosterone derivatives on endometrial Ishikawa cells. 757 23

It has been proposed that the biosynthesis of estrogens by the human endometrium may be of physiological significance during the menstrual cycle. Local estrogen production was also suggested to be important in the development of endometrial cancer; however, the presence or absence of aromatase enzyme activity in normal human endometrium is controversial. To address this issue, we used a sensitive technique capable of detecting mRNA transcripts present in only very low copy number. The polymerase chain reaction linked to reverse transcription (RT-PCR) was used to evaluate the presence or absence of aromatase cytochrome P450 (P450arom) transcripts in endometrial tissues (n = 7) and endometrial stromal cells (n = 9) under various culture conditions. RNA was isolated from four proliferative and three secretory tissue samples and from cultured endometrial stromal cells isolated from seven proliferative and two secretory endometria. Five sets of cultures were treated with medroxyprogesterone acetate (MPA), estradiol (E2), and forskolin. Additionally, RNA was isolated from decidualized endometrium obtained from a patient with tubal pregnancy. A single stranded cDNA was synthesized from total RNA using Moloney murine leukemia virus reverse transcriptase and a P450arom-specific oligonucleotide. The single stranded cDNA was used as a template for PCR and was amplified for 20-35 cycles using P450arom-specific primers. RNA from adipose tissue and placenta was amplified to provide positive controls, whereas myometrial RNA was used as a negative control. In two experiments involving two endometrial tissues and three sets of cells in culture, a rat P450arom cRNA was coamplified in each sample as an internal control to demonstrate that the remote possibility of RT-PCR failures in individual test samples cannot account for our negative results. By Southern or slot blot hybridization of the amplified fragments using human and rat P450arom-specific probes, we found no evidence for the presence of P450arom transcripts in normal endometrium, decidualized endometrium, or endometrial stromal cells in culture. In our hands, assay of aromatase activity using [3H]water release from [3H]androstenedione by endometrial stromal cells in culture treated with MPA and E2, did not reveal any detectable aromatase activity. The same cells responded to MPA plus E2 treatment by a significant increase in PRL secretion into the culture medium. Presently, RT-PCR is the most sensitive method available for the detection of specific mRNA species in low copy numbers. These findings are indicative of the absence of P450arom transcripts in normal human endometrium.
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PMID:Polymerase chain reaction amplification fails to detect aromatase cytochrome P450 transcripts in normal human endometrium or decidua. 768 41


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