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

A test is described for the evaluation of hormone sensitivity of endometrial cancer in vivo. The concentrations of progesterone and estradiol receptors, and the activities of ornithine-decarboxylase and 17 beta-hydroxysteroid oxido-reductase enzymes have been measured in the tumor, before and after administration of the anti-estrogen tamoxifen. The responses observed, in particular the increase of progesterone receptor, could allow a more rational approach to hormonal therapy of endometrial cancer.
 ...
PMID:[Response to an antiestrogen as a criterion for hormonal sensitivity of endometrial cancer]. 11 15

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).
 ...
PMID:Heterosteroids and drug research. 184 48

Tamoxifen (TXF), a triphenylethylene antiestrogen, is the major therapeutic agent for breast cancer. In rare cases, TXF treatment appears to increase incidence of endometrial cancer. Also in rats, TXF was found to induce hepatocellular carcinoma. Previous studies suggested that metabolism of TXF may contribute to its antiestrogenic and anticancer activity. The current study demonstrates a novel route of TXF metabolism. TXF is metabolized by rat and human liver microsomes into a reactive intermediate (txf*) which binds irreversibly to microsomal proteins. The binding requires NADPH and O2 and is inhibited by CO, inhibitors of P-450, and antibodies to rat NADPH-P450 reductase, indicating catalysis by P450. Phenobarbital treatment of rats markedly increases binding, suggesting the involvement of induced P450s. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of proteins from incubation of [14C] TXF with phenobarbital-treated microsomes exhibits a major radiolabeled zone which corresponds to a molecular weight of approximately 54,000, suggesting binding to a P-450. Cysteine and glutathione inhibited the binding of TXF without significantly affecting P-450-mediated metabolism of TXF, possibly by reacting with txf* or by competing for the same binding sites. Exposure of phenobarbital-treated microsomes and control-microsomes to 50 degrees C for 90 s, which inactivates the flavin-containing monooxygenase (FMO), diminished binding and pH 8.6 enhanced binding. Also, alternate FMO substrates inhibited binding. These findings indicate that P-450 and possibly FMO catalyze the reactions leading to the formation of txf*. However, incubations with single-labeled and dual-radiolabeled tamoxifen or with [14C]TXF-N-oxide demonstrated that monodesmethyl-TXF and TXF-N-oxide, the principal P-450 and FMO-mediated metabolites, respectively, are not on the major route of txf* formation, indicating that txf* could not be an aldehyde derived from tamoxifen nitrone. Thus, though the structure of txf* was not characterized, certain possibilities were excluded. Speculations on the structure of txf* and on its possible pharmacological and toxicological activity are presented.
 ...
PMID:Cytochrome P-450-mediated activation and irreversible binding of the antiestrogen tamoxifen to proteins in rat and human liver: possible involvement of flavin-containing monooxygenases in tamoxifen activation. 193 68

Many of the most common cancers occur in sites that are under hormonal regulation by the steroid sex hormones. These include the breast, ovary, endometrium and possibly the colon for women, and the prostate and testes for men. Much information on chemoprevention of these cancers has accrued indirectly as a result of the use of estrogens and progestagens for contraception or postmenopausal hormone replacement therapy. Estrogen-based contraceptives clearly reduce the risk of ovarian cancer, but without an opposing progestagen they increase the risk of endometrial cancer. Progestagens reduce the risk of endometrial cancer and when used premenopausally appear to be able to more than counteract the carcinogenic effect of exogenous estrogens at this site. The effect of oral contraceptives on breast cancer appears to be quite minimal, but probably increases risk when taken for long periods at a young age. Recent studies suggest that the use of an agonist of leuteinizing hormone releasing hormone as a contraceptive may reduce the risk of breast cancer. Estrogens used in postmenopausal hormone replacement therapy increase the risk of both breast and endometrial cancer, but addition of a progestagen may counteract the increased risk to the endometrium. The agent most intensively under study for breast cancer prevention is tamoxifen, which has proven effectiveness as a therapeutic agent. When taken for more than two years it has been shown to reduce the occurrence of new contralateral tumours by about 50% in women who have had breast cancer. Three large international trials are currently evaluating its role in a preventive setting. For men, interest has centred on the use of 5 alpha-reductase inhibitors to block the prostatic conversion of testosterone to dehydrotestosterone and potentially inhibit the development of prostate cancer. The 5 alpha-reductase inhibitor finasteride is currently under test in a prevention trial.
 ...
PMID:Medicinal drugs with hormonal activity as chemopreventive agents. 892 22

Tamoxifen is a major drug used for adjuvant chemotherapy of breast cancer; however, its use has been associated with a small but significant increase in risk of endometrial cancer. In rats, tamoxifen is a hepatocarcinogen, and DNA adducts have been observed in both rat and human tissues. Tamoxifen has been shown previously to be metabolized to reactive products that have the potential to form protein and DNA adducts. Previous studies have suggested a role for P450 3A4 in protein adduct formation in human liver microsomes, via a catechol intermediate; however, no clear correlation was seen between P450 3A4 content of human liver microsomes and adduct formation. In the present study, we investigated the P450 forms responsible for covalent drug-protein adduct formation and the possibility that covalent adduct formation might occur via alternative pathways to catechol formation. Recombinant P450 3A4 catalyzed adduct formation, and this correlated with the level of uncoupling in the P450 incubation, consistent with a role of reactive oxygen species in potentiating adduct formation after enzymatic formation of the catechol metabolite. Whereas P450s 1A1, 2D6, and 3A5 generated catechol metabolite, no covalent adduct formation was observed with these forms. By contrast, P450 2B6, 2C19, and rat liver microsomes catalyzed drug-protein adduct formation but not catechol formation. Drug protein adducts formed specifically with P450 3A4 in incubations using membranes isolated from bacteria expressing P450 3A4 and reductase, as well as in reconstitutions of purified 3A4, suggesting that the electrophilic species reacted preferentially with the P450 enzymes concerned.
 ...
PMID:Bioactivation of tamoxifen by recombinant human cytochrome p450 enzymes. 1201 81

The steroid hormones are recognized and fixed by special cytoplasmic proteins in the target tissue called receptors. Most circulating natural steroids are tied to transport proteins. Estradiol and progesterone are active as such in the receptor cells, but testosterone is transformed into dihydrotestosterone in situ under the influence of the enzyme 5 alpha reductase before combining with the receptor. Receptivity may be exacerbated or reduced. Exacerbation is particularly likely when physiological control mechanisms are deficient. Testosterone has a biological effect at the level of the Wolfian apparatus in the embryo and in the muscle and bone of the adult. The activity of perineal 5 alpha reductase implicated in these phenomena and the hepatic 5 alpha reductase activity implicated in the degradation of testosterone are found in both sexes and are under genetic influence independent of the male hormone. Problems in receptivity to the male hormone are well known to clinicians. Hirsutism, whatever its cause, is always associated with great cutaneous 5 alpha reductase activity. The use of antiandrogens derived from synthetic progestagens has transformed treatment of hirsutism. Male pseudohermaphrodism may be secondary to an insufficient testosterone production or to primary resistence to the male hormone, in which case the plasma concentration of testosterone is always greater than normal. The characteristic case is of a deficit of 5 alpha reductase and feminization of the testicle. 5 alpha reductase deficiency causes sexual ambiguity at birth. Absence of the testosterone receptor at both the perineal and public levels explains why attempts to treat these disorders with high doses of testosterone or dihydrotestosterone always fail. Problems in receptivity to the male hormone have been found to cause other pathologies, such as severe oligospermia. The quantity of estradiol and progesterone receptors varies according to the volume of circulating estradiol and of progesterone. Progesterone is a natural antiestrogen; it limits the activity of estradiol by favoring the transformation of estradiol into estrone and decreases the synthesis of estradiol receptors. The normal endometrium may become hyperplasic after menopause, the 1st stage in development of endometrial cancer. Continuous estrogen stimulation not countebalanced by progesterone permits the transformation. Study of estradiol and progesterone receptors in mammary fibroadenomas has shown that estradiol receptors increase to a maximum in the preovulatory period and diminish in the luteal phase. The increase in estradiol is followed by an increase in progesterone receptors. Since 1971 it has been apparent that breast cancer susceptible to improvement by hormonal treatment were rich in estrogen receptors.
 ...
PMID:[Receptivity to the sex steroids, physiopathological aspects]. 1231 77

Aldo-keto reductase family 1, member B10 (AKR1B10), an enzyme that converts retinals into retinols is known to detect in non-small cell lung carcinoma (squamous cell- and adeno-carcinomas), but is barely expressed in normal tissues. Since these types of carcinoma occur frequently in the uterus (like in the lung), AKR1B10 may also be overexpressed in two major types of uterine cancer, cervical cancer (CC), and endometrial cancer (EMC). The objective of this study is to investigate AKR1B10 expression in uterine cancer and to analyze its clinical significance. In samples from uterine cancer patients, AKR1B10 was detected in 6 out of 30 (20.0%) CC cases and 6 out of 38 (15.8%) EMC cases. Statistical analysis indicated that AKR1B10 expression was associated with tumor recurrence after surgery and keratinization of squamous cell carcinoma only in CC. Although retinol (a metabolic product by AKR1B10) was observed in the normal epithelium, the molecule was not observed in cancer cells of AKR1B10-positive CC samples suggesting that the recurrence in CC may not depend on the convert of retinals into retinols via AKR1B10, a potential indicator in the management of patients with CC.
 ...
PMID:Aldo-keto reductase family 1, member B10 in uterine carcinomas: a potential risk factor of recurrence after surgical therapy in cervical cancer. 1742 79

Aldo-keto reductase 1C1 is a hydroxysteroid dehydrogenase that inactivates progesterone by converting it to 20alpha-hydroxyprogesterone. It also inactivates 3alpha,5alpha-tetrahydroprogesterone, an allosteric modulator of the gamma-aminobutyric acid receptor that has anaesthetic, analgesic, anxiolytic and anti-convulsant effects. Inhibitors of aldo-keto reductase 1C1 are thus very interesting as potential agents for the treatment of endometrial cancer, premenstrual syndrome, catamenial epilepsy, and depressive disorders, and for the maintenance of pregnancy. We have used the molecular docking program eHiTS for virtual screening of 1990 compounds from the National Cancer Institute "Diversity Set". Fifty compounds with the highest predicted binding energies were then evaluated in vitro. Three structurally diverse hits were obtained that inhibit aldo-keto reductase 1C1 in the low micromolar range of IC(50) values. These hits represent promising starting points for structural optimization in hit-to-lead development.
 ...
PMID:Discovery of new inhibitors of aldo-keto reductase 1C1 by structure-based virtual screening. 1876 69

AKR1C3 (also known as 17beta-hydroxysteroid dehydrogenase type 5 or 3alpha-hydroxysteroid dehydrogenase type 2) functions as a 3-keto, 17-keto and 20-ketosteroid reductase and as a 3alpha-, 17beta- and 20alpha-hydroxysteroid oxidase. Relatively high mRNA expression of AKR1C3 was found in human prostate and mammary gland where it is implicated in regulating ligand access to the androgen and estrogen receptor, respectively. AKR1C3 is an interesting target for the development of agents for treating hormone-dependent forms of cancer like prostate cancer, breast cancer, and endometrial cancer. However, only a few clinically promising and selective inhibitors have been reported so far. Very potent inhibitors of AKR1C3 are the non-steroidal anti-inflammatory drugs, e.g. indomethacin or flufenamic acid. Also dietary phytoestrogens such as coumestrol, quercetin, and biochanin were reported to inhibit the enzyme in low micromolar concentrations. In this study, some dietary flavonoids and other phenolic compounds were tested for their ability to specifically inhibit AKR1C3. Carbonyl reduction of the anticancer drug oracin, which is a very good substrate for AKR1C3 and which could be well monitored by a sensitive HPLC system with fluorescence detection, was employed to determine the inhibitory potency of the compounds. Our results reveal that AKR1C3 could be potentially un-competitively inhibited by 2'-hydroxyflavanone, whose IC(50) value of 300nM is clinically promising. Moreover, since the inhibition is selective towards AKR1C3, 2'-hydroxyflavanone could be useful for treating or preventing hormone-dependent malignancies like prostate and breast cancer.
 ...
PMID:AKR1C3 as a potential target for the inhibitory effect of dietary flavonoids. 1900 64

Endometrial cancer, the most common gynecological malignancy in western countries, is characterized by a favorable prognosis. Nonetheless, deep myometrial invasion correlates with more undifferentiated tumors, lymph-vascular invasion, node involvement and decreased global survival. We have described previously the Ets family member ERM/ETV5 specifically upregulated in endometrial endometrioid carcinoma (EEC) associated with myometrial infiltration. To understand the role of this transcription factor during myometrial infiltration, we analyzed by two-dimension differential gel electrophoresis (2D-DIGE) technology those proteins whose expression was altered in endometrial cell lines stably overexpressing ERM/ETV5. Pathway analysis pointed to actin regulation and transforming growth factor beta and progesterone signaling as processes regulated by ERM/ETV5. In addition, we characterized the specific upregulation of the nuclear dehydrogenase/reductase Hep27 as well as its ERM/ETV5-dependent mitochondrial localization. Further functional studies demonstrated a protective role of Hep 27 against apoptosis induced by oxidative stress. Overall, the ETV5-related proteomic approach performed in the Hec-1A cell line reinforces a role of this transcription factor in the regulation of the migratory and invasive tumor behavior and points to a modulated response to oxidative stress associated with the promotion of invasion in endometrial cancer. Unraveling the molecular events in EEC associated with the initiation of tumor invasion would represent an obvious improvement in the pursuit of rational targets for the onset of metastasis. This knowledge would also be a valuable tool for the molecular stratification of patients since myometrial affectation determines an increase in the rate of recurrence after a first surgical treatment and a decrease in 5 year survival.
 ...
PMID:Proteomic approach to ETV5 during endometrial carcinoma invasion reveals a link to oxidative stress. 1944 6


1 2 3 Next >>