Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Patients treated for dysfunctional uterine bleeding are separated into two groups: those with acute bleeding episodes and those with chronic repetitive bleeding problems. An acute bleeding episode is best controlled with the use of high-dose estrogen. A curettage is indicated for patients with acute bleeding resulting in hypovolemia, and a curettage or hysteroscopically directed biopsies is indicated for women with risk factors for endometrial cancer who have persistent bleeding problems. The management of anovulatory dysfunctional uterine bleeding is determined by the needs of the patient. In the adolescent medroxyprogesterone acetate is administered orally once a day for 10 days each month for > or = 3 months, and the patient is monitored closely thereafter. Oral contraceptives are used for women of reproductive age with anovulatory bleeding episodes who also require contraception. Clomiphene citrate is used for women of reproductive age with anovulatory bleeding who want to conceive. Oral medroxyprogesterone acetate is administered 10 days each month for 6 months for the treatment of anovulatory dysfunctional uterine bleeding alone in this age group. For the perimenopausal patient dysfunctional uterine bleeding may be treated by the administration of cyclic progestin or cyclic conjugated equine estrogens for 25 days with the concomitant administration of medroxyprogesterone acetate for days 18 to 25. The perimenopausal patient with dysfunctional uterine bleeding who is a nonsmoker and does not have evidence of vascular disease may also be treated with low-dose combination oral contraceptives. The long-term treatment for women with ovulatory dysfunctional uterine bleeding is the most difficult type of dysfunctional uterine bleeding to manage. The long-term therapy is directed at the reduction in menstrual blood loss. For these patients prolonged progestin use, oral contraceptives, nonsteroidal antiinflammatory drugs, antifibrinolytic agents, danazol, and as a last resort gonadotropin-releasing hormone agonists are part of the therapeutic armamentarium. A combination of two or more of these agents is often required to successfully control the abnormal bleeding. For patients who no longer desire future fertility and have associated pelvic pathologic disorders or for those who fail all medical regimens, surgical therapy may be considered. Either hysterectomy or endometrial ablation has been used. Patients with von Willebrand's disease and excessive menstrual blood loss may be misdiagnosed as having dysfunctional uterine bleeding. van Willebrand's disease is the most common bleeding disorder and is present in approximately 1% of the population. It is much more common than previously recognized. There are improved diagnostic tests to identify this disorder and, most important, there is a high-concentration desmopressin acetate nasal spray available as treatment that does not involve the risk of transmission of hepatitis and human immunodeficiency virus.
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PMID:Management of abnormal uterine bleeding. 882 63

We studied the involvement of annexin V in the antiproliferative effects of gonadotropin-releasing hormone (GnRH) agonists on human endometrial cancer cell line HHUA. HHUA cell line expressed mRNA for GnRH receptors as assessed by reverse transcriptase-PCR with oligonucleotide primers. In the presence of buserelin, the proliferation of this cell line was significantly (P < 0.01) reduced to 60% of control after 72 hr. Peak intracellular concentrations of annexin V, equivalent to about twice the control value, were obtained after 48 hr exposure to buserelin. Intracellular annexin V concentration was increased not only by buserelin, but also by protein kinase C (PKC) activator. However, there was no increase in intracellular annexin V concentration when cells were incubated with PKC inhibitor before the addition of buserelin. The results suggest that GnRH agonists inhibit cell proliferation by increasing intracellular concentrations of annexin V, an effect mediated by the activation of PKC.
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PMID:Involvement of annexin V in antiproliferative effects of gonadotropin-releasing hormone agonists on human endometrial cancer cell line. 926 65

Conjugation of gonadotropin-releasing hormone (GnRH) analogues GnRH-III, MI-1544, and MI-1892 through lysyl side chains and a tetrapeptide spacer, Gly-Phe-Leu-Gly (X) to a copolymer, poly(N-vinylpyrrolidone-co-maleic acid) (P) caused increased antiproliferative activity toward MCF-7 and MDA-MB-231 breast, PC3 and LNCaP prostate, and Ishikawa endometrial cancer cell lines in culture and against tumor development by xenografts of the breast cancer cells in immunodeficient mice. MCF-7 cells treated with P-X-1544 and P-X-1892 displayed characteristic signs of apoptosis, including vacuoles in the cytoplasm, rounding up, apoptotic bodies, bleb formation, and DNA fragmentation. Conjugates, but not free peptides, inhibited cdc25 phosphatase and caused accumulation of Ishikawa and PC3 cells in the G2/M phase of the cell cycle after 24 h at lower doses and in the G1 and G2 phases after 48 h. Since P-X-peptides appear to be internalized, the increased cytotoxicity of the conjugates is attributed to protection of peptides from proteolysis, enhanced interaction of the peptides with the GnRH receptors, and/or internalization of P-X-peptide receptor complexes so that P can exert toxic effects inside, possibly by inhibiting enzymes involved in the cell cycle. The additional specificity of P-X-peptides compared with free peptides for direct antiproliferative effects on the cancer cells but not for interactions in the pituitary indicates the therapeutic potential of the conjugates.
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PMID:Gonadotropin-releasing hormone analogue conjugates with strong selective antitumor activity. 1005 47

The LHRH analogues are used very much in gynecological practice, mostly for a long treatment periods. The menopausal side effects occur often and causes the patients to withdraw from treatment. The GnRh analogues are used for the treatment of endometriosis, uterine fibroids, for breast cancer, and pre and post operatively as hormonal therapy for endometrial cancer. 12 patients were given combined vaginal Ovestin and GnRh analogues (Zoladex). Another 12 patients were taking GnRh analogues alone without Ovestin creme, and this group searched as a control group. The group with the Ovestin had less side effects than the control group. This difference was statistically significant about the cervicovaginal symptoms (p less than 0.01). The treatment with vaginal estrogenes can better and improve the tolerance to therapy with GnRh analogues.
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PMID:[The use of Ovestin to overcome the side effects of treatment with GnRH agonists (Zoladex)]. 1036 48

Gonadotropin-releasing hormone (GnRH) has been shown to have an inhibitory effect on the growth of several hormone-dependent human tumors. We have treated a human endometrial cancer cell line which expresses GnRH receptor with GnRH analog, D-Trp6-LHRH, in order to study whether there are differences in cell cycle kinetic response. Flow cytometric analysis revealed that cultured carcinoma cells showed a cell cycle arrest at the G1-S transition after treatment with 10 microM D-Trp6-LHRH for 36 h. Western blot analysis showed that the level of p16 protein was obvious following 24 h of D-Trp6-LHRH treatment. These results suggest that the mechanism by which GnRH inhibits the growth of endometrial carcinoma cells may include effects on cell cycle arrest.
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PMID:Cell cycle arrest in endometrial carcinoma cells exposed to gonadotropin-releasing hormone analog. 1036 62

Six endometrial cancer cell lines (Ishikawa, EIIL, HEC1A, 6, 50 and 59), one breast cancer cell line (MCF-7) and two ovarian cancer cell lines (OVHS-1, HRA) were treated for 24 or 168 h with a gonadotropin-releasing hormone (GnRH) analogue, Buserelin acetate, and the cellular growth profile was studied. All these cell lines except for the HRA line had positive GnRH receptor mRNA expression detected by reverse transcriptase polymerase chain reaction. GnRHa suppressed cell growth after 168 h of exposure, but not after 24 h. Suppression of cell growth by the exposure to cis-platinum (CDDP, 10 nM for 24 h) was significantly increased in the presence of GnRHa for 168 h. The mechanism of this growth inhibition was tested by examining both RNA components of human telomerase (hTR) expression and telomerase activity. The results showed that GnRHa inhibits telomerase activity without altering the RNA component of telomerase expression. The present data suggest that GnRH analogue may modulate endometrial, breast and ovarian cancer cell growth through modifying the telomerase activity. Since GnRHa increased the cytotoxic effects of CDDP and GnRHa is a compound of high patient compliance, the value of GnRHa as a tumor sensitizer to CDDP should be further tested in clinical trials.
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PMID:In vitro effects of gonadotropin-releasing hormone (GnRH) analogue on cancer cell sensitivity to cis-platinum. 1038 Nov 37

The signaling pathway through which LHRH acts in endometrial and ovarian cancers is distinct from that in the anterior pituitary. The LHRH receptor interacts with the mitogenic signal transduction of growth factor receptors, resulting in down-regulation of expression of c-fos and proliferation. Only limited data are available on the cross-talk between LHRH receptor signaling and inhibition of mitogenic signal transduction. The present experiments were performed to analyze in endometrial and ovarian cancer cells: 1) whether mutations or splice variants of the LHRH receptor are responsible for differences in LHRH signaling, 2) the coupling of G protein subtypes to LHRH receptor, 3) the phosphotyrosine phosphatase (PTP) activation counteracting growth factor receptor tyrosine kinase activity. For these studies, the well characterized human Ishikawa and Hec-1A endometrial cancer cell lines and human EFO-21 and EFO-27 ovarian cancer cell lines were used, which express LHRH and its receptor. 1) Sequencing of the complementary DNA of the LHRH receptor from position 31 to position 1204, covering the complete coding region (position 56 to position 1042) showed that there are neither mutations nor splice variants of the LHRH receptor transcript in Ishikawa and Hec-1A endometrial cancer cells or in EFO-21 and EFO-27 ovarian cancer cells. 2) All analyzed cell lines except for the ovarian cancer cell line EFO-27 expressed both G proteins, alpha(i) and alpha(q), as shown by RT-PCR and Western blotting. In the EFO-27 cell line only G protein alpha(i), not G protein alpha(q), expression was found. Cross-linking experiments using disuccinimidyl suberate revealed that in the cell lines expressing G protein alpha(i) and G protein alpha(q), both G proteins coupled to the LHRH receptor. Inhibition of epidermal growth factor (EGF)-induced c-fos expression by LHRH, however, was mediated through pertussis toxin (PTX)-sensitive G protein alpha(i). Moreover, LHRH substantially antagonized the PTX-catalyzed ADP-ribosylation of G protein alpha(i). 3) Using a phosphotyrosine phosphatase assay based on molybdate-malachite green, treatment of quiescent EFO-21 and EFO-27 ovarian cancer cells and quiescent Ishikawa and Hec-1A endometrial cancer cells with 100 nM of the LHRH agonist triptorelin resulted in a 4-fold increase in PTP activity (P < 0.001). This effect was completely blocked by simultaneous treatment with PTX, supporting the concept of mediation through G protein alpha(i). As shown by quantitative Western blotting, EGF-induced tyrosine autophosphorylation of EGF receptors was reduced 45-63% after LHRH (100 nM) treatment (P < 0.001). This effect was completely blocked using the PTP inhibitor vanadate (P < 0.001). These results demonstrate that mutations or splice variants of the LHRH receptor in human endometrial and ovarian cancer cells are not responsible for the different signal transduction compared with that in pituitary gonadotrophs. We provide evidence that the tumor LHRH receptor couples to multiple G proteins, but the antiproliferative signal transduction is mediated through the PTX-sensitive G protein alpha(i). The tumor LHRH receptor activates a PTP counteracting EGF-induced tyrosine autophosphorylation of EGF receptor, resulting in down-regulation of mitogenic signal transduction and cell proliferation.
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PMID:Antiproliferative signaling of luteinizing hormone-releasing hormone in human endometrial and ovarian cancer cells through G protein alpha(I)-mediated activation of phosphotyrosine phosphatase. 1135 84

In view of advances in treatment of certain hormone-dependent cancers with analogues of gonadotropin-releasing hormone (Gn-RH), this study was undertaken to establish the signal transduction events interacting with Gn-RH receptor in a cell-free system prepared from human ovarian mucinous cystadenocarcinoma samples. A high affinity specific binding (Kd=8 x 10-9 M) of [3H] Gn-RH was demonstrated in two from two plasma membrane preparations. Gn-RH showed no effects on the rate of protein phosphorylation from [gamma-32P] adenosine triphosphate in the plasma membrane preparations. On the other hand, incubation of plasma membrane isolated form [3H]inositol-labeled specimens with Gn-RH in the presence of guanosine thiotriphosphate resulted in the rapid production of inositol phosphates. The Gn-RH effects was concentration-dependent, and half-maximal activation occurred with 1-3 nm Gn-RH. The Gn-RH-stimulated membrane event was observed in all plasma membrane isolations tested, but not in those from uterine endometrial carcinoma of a given case. These results provide the first direct evidence that Gn-RH receptor is coupled to phosphoinositide hydrolysis but not to certain membrane protein phosphorylation/dephosphorylation in ovarian carcinoma plasma membrane. Though the functional role of this event in human ovarian cancer is still obscure, it might be part of a possible point of attack for therapeutic approaches using Gn-RH analogues in this malignancy.
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PMID:Gonadotropin-releasing hormone stimulates phospholipase C but not protein phosphorylation/dephosphorylation in plasma membrane from human epithelial ovarian cancer. 1157 63

In premenopausal women ovaries are the major sites of estrogen production, while in postmenopausal women estrogen is produced by aromatization of ovarian and adrenal androgens in extragonadal sites, mostly in adipose tissue. Aromatase is a cytochrome P450 hemoprotein-containing enzyme complex that catalyzes the rate-limiting step in the conversion of androstenedione and testosterone to estrone and estradiol (E2). Aromatase inhibitors (AIs) have been developed primarily for use in either natural or surgical postmenopausal patients. In premenopausal women, the ovary can overcome the estrogen blockade by reflex increments of luteinizing hormone (LH) and follicle stimulating hormone (FSH), so AIs must be combined with a gonadotropin releasing hormone (GnRH) agonist to prevent the reflex LH and FSH increments. In advanced hormone-dependent breast cancer treatment, AIs have been shown to be superior to tamoxifen. Preliminary evidence also suggests superiority in the adjuvant, neoadjuvant settings and also for breast cancer prevention. AIs have been used in infertility and can increase ovulation rate. Reducing FSH dose, estrogen levels, improving response to FSH, implantation rates, and developing multiple follicles that can be used in in vitro maturation procedures are potential areas that AIs might be used in in assisted reproductive technologies (ART), besides simple ovulation induction. AIs are reported to be successful in treatment of endometriosis, an estrogen-dependent process. The use of AIs in gynecomastia, puberte precox, leiomyoma uteri, some estrogen-dependent cancers (ovarian), endometrial cancer and male infertility are reported; some of the results are promising but more clinical trials are needed. AIs are predicted to become the gold standard in the treatment of estrogen-dependent diseases in reproductive medicine in the near future.
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PMID:Aromatase inhibitors: possible future applications. 1525 40

Naturally occurring isoforms of the decapeptide gonadotropin-releasing hormone (GnRH) share residues 1-4 and 9-10. lGnRH-III, the third isoform isolated in the sea lamprey has no endocrine effect in mammals but shows a direct antiproliferative effect on human breast, prostate and endometrial cancer cell lines. To investigate these features, residues 5-8 of lGnRH-III were systematically replaced with Ala. The ability of the synthetic analogs to interact with receptors on MDA-MB 231 human breast cancer cells and their effect on the growth of the same cell line were investigated. [Ala6]lGnRH-III and [Ala7]lGnRH-III have neither receptor binding nor antiproliferative activity. Replacement of His5 with Ala resulted in an analog that binds to the receptor but does not have antiproliferative activity. The results are in agreement with previous reports that modifications of Lys at position 8 are well tolerated.
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PMID:Importance of the central region of lamprey gonadotropin-releasing hormone III in the inhibition of breast cancer cell growth. 1565 48


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