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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen is the major therapeutic agent for the treatment of hormone-dependent breast cancer. Tamoxifen treatment appears to be associated with an increased incidence of endometrial carcinoma in humans and hepatocellular carcinoma in rats. These carcinogenic effects of tamoxifen might be induced by the formation of a tamoxifen reactive intermediate that binds covalently to macromolecules. Liver microsomal cytochrome P450s (CYPs) catalyze the metabolism of tamoxifen, forming a reactive intermediate that binds irreversibly to microsomal proteins, primarily to a 54 kDa protein (Mani, C. and Kupfer, D., Cancer Res., 51, 6052-6058, 1991). The current study identifies the P450 enzymes that catalyze the activation of tamoxifen to a reactive intermediate in rats and humans. Among the species examined, rats, chickens and humans demonstrate low tamoxifen binding activity, ranging from 0.1 to 0.4 nmol bound/mg protein/h. In contrast, hamsters and mice exhibit high binding, 1.2 and 1.6 nmol/mg protein/h respectively. Treatment of male rats with phenobarbital or pregnenolone-16 alpha-carbonitrile (PCN) markedly elevated the binding of tamoxifen to liver microsomal proteins. Methylcholanthrene treatment had no effect on binding. These findings suggested the involvement of CYP3A in catalysis of the covalent binding. Alternate substrates of CYP3A, cortisol and erythromycin, inhibited tamoxifen binding in liver microsomes from PCN- and phenobarbital-treated rats. Treatment of rats with troleandomycin (TAO), an inducer of CYP3A, followed by the dissociation of the TAO-CYP3A complex, elevated the covalent binding to liver microsomes approximately 3-fold. Antibodies against rat CYP3A1 strongly inhibited tamoxifen binding to liver microsomes from PCN- and phenobarbital-treated rats, whereas the antibodies anti-CYP2B1/2B2 did not inhibit binding. In humans, tamoxifen binding was inhibited by the anti-rat CYP3A1 IgG and also by alternate substrates of CYP3A. These results indicate that the activation of tamoxifen to a reactive intermediate by rat and human liver microsomes is principally catalyzed by CYP3A enzymes.
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PMID:Involvement of cytochrome P4503A in catalysis of tamoxifen activation and covalent binding to rat and human liver microsomes. 800 Dec 26

Tamoxifen is one of the most important treatments for breast cancer, especially in postmenopausal patients. It acts primarily as an anti-estrogenic agent, due to its cytoplasmic estrogen receptor binding capacity. However, it also exerts a mild estrogenic effect. Since the prolonged use of estrogen has been reported to increase the rate of benign and malignant changes in the endometrium, we evaluated whether there is a correlation between tamoxifen therapy and endometrial benign and malignant conditions. The study group comprised 95 patients with breast cancer who were treated with tamoxifen. No control group was examined. Patients underwent vaginal ultrasonography and endometrial biopsy in order to evaluate any changes in the endometrium occurring during tamoxifen therapy. Pathological changes were observed in 14 patients, 13 of whom were treated with tamoxifen for more than 12 months. Of these women, 3 were diagnosed with endometrial cancer, 3 had mild dysplasia, 3 had endometrial hyperplasia, and 4 had a benign endometrial polyp. Our findings indicate a significant correlation between long-term tamoxifen administration and endometrial proliferation. We therefore recommend that women treated with tamoxifen for more than 12 months have an annual vaginal ultrasonography and endometrial biopsy.
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PMID:The effect of tamoxifen on the endometrium. 840 Mar 18

The results of assay of receptorial status of tumor in 152 primary patients with endometrial carcinoma are presented. It was shown that a 10-day course of preoperative Tamoxifen therapy (course dose 0.6 g) was able to increase significantly concentrations of nuclear estradiol receptors and cytoplasmatic progesterone receptors in the tumor. This phenomenon followed morphological changes in the tumor and was established in both hormone dependent type (72.7%) and hormone independent type of endometrial carcinoma (45.5%). The assay of the dynamics of receptorial status of primary endometrial carcinoma under influence of Tamoxifen before surgery might be an informative test for selection of sensitive patients with poor prognosis for prolonged hormone therapy in remission to prevent development of recurrencies.
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PMID:Criteria of endometrial carcinoma sensitivity to hormone therapy: pathogenetic type of the disease and the tumor reaction to tamoxifen. 850 Apr 97

In a prospective and randomized study comprising 540 primary endometrial carcinoma patients the influence of adjuvant hormone therapy by Oxyprogesterone caproate (OPC) and by its combination with Tamoxifen on the corrected survival rates after surgical and combined (surgical and irradiation) therapy was investigated. As was shown OPC administered preoperatively and after surgical and combined therapy from 6 up to 36 months increased the corrected survival rates as compared with that in patients who did not receive hormone treatment. Combination of OPC and Tamoxifen administered additionally to surgical and combined therapy increase the corrected survival rate at the 5th year by 19%. One can conclude that adjuvant hormone therapy in endometrial carcinoma patients who have unfavourable prognosis of the disease must be administered for not less than 3 years in order to obtain prolongation of remission of the disease.
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PMID:Favourable influence of adjuvant hormone therapy by oxyprogesterone caproate (OPC) and by its combination with tamoxifen on 5-year survival rate of surgical and combined treatment of primary endometrial carcinoma patients. 850 Apr 99

A high percentage of endometrial carcinomas contain oestrogen and progesterone receptors. For endocrine therapy of recurrent endometrial carcinoma, only high-dose progestins are in clinical use. As, therefore, the development of new endocrine treatment strategies is of great interest, suitable animal models for this tumour are essential. Up to now, only human tumour xenografts transplanted in immune-deficient nude mice, but no syngeneic in vivo tumour models, have been available. In the present article we describe the hormone sensitivity of the EnDA endometrial adenocarcinoma of the DA/Han rat growing as s.c. implants in DA/Han rats and athymic nude mice in serial passage. In both species, the tumour expresses oestrogen, but no progesterone receptors. Transplanted in DA/Han rats or nude mice, ovariectomy reduced tumour weight by 64% and 46% respectively. In both species substitution of ovariectomized animals with oestradiol restored tumour weights to intact control levels. Oestradiol substitution of intact animals did not further enhance tumour growth. The growth of the primary tumour was inhibited by medroxyprogesterone acetate (MPA) at a dose of 100 mg/kg by 67% and by tamoxifen at a dose of 20 mg/kg by 38%. Lung metastases were regularly seen in both species, although to a lesser extent in nude mice than in DA/Han rats. Tamoxifen treatment did not alter the number of lung metastases, whereas MPA or ovariectomy produced a significant reduction in the number of lung metastases. The EnDA endometrial carcinoma of the DA/Han rat with respect to its oestrogen sensitivity, oestrogen receptor expression, morphology and metastatic growth, grossly resembles a typical endometrial adenocarcinoma and can therefore be regarded as a useful in vivo experimental model for the evaluation of new endocrine treatment strategies.
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PMID:The EnDA endometrial adenocarcinoma: an oestrogen-sensitive, metastasizing, in vivo tumour model of the rat. 850 35

22 patients with endometrial cancer were studied. Twelve (54.5%) between 45 and 66 years were treated for six days before surgery with 160 mg per os of Megestrol acetate administered twice daily plus Beta interferon 3,000,000 IU- on alternate days for a week, plus Tamoxifen--two cp of 10 mg daily for six days. Before and after surgery and associated medical therapies the steroid receptor values (ER and PgR) were checked. After treatment an average increase was observed of the ER (19 fmol/mg) and PgR (17 fmol/mg). Of the twelve patients one died of a stroke during the study (8.33%); five (41.67%) showed complete remission (CR); four (33.34%) a partial remission (PR) and two (16.67%) were not responders (NR).
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PMID:Tamoxifen, megestrol acetate, and beta interferon in endometrial cancer. 853 66

The biological rationale and extensive clinical experience with the breast cancer drug tamoxifen make it the agent of choice for testing as a breast cancer preventive. However, concerns (Jordan and Morrow, Eur J Cancer, in press) about development of endometrial cancer in patients and liver tumors in rats with tamoxifen has encouraged the investigation of other antiestrogens. At present no compounds are available to replace tamoxifen, but two triphenylethylenes, toremifene and droloxifene, have been tested in postmenopausal women to treat advanced breast cancer. The response rates are similar to those observed with tamoxifen (i.e., approximately 35% [CR+PR] in unselected patients), although dosage regimens of the new antiestrogens are higher than the 20 mg tamoxifen required daily. Doses of up to 200 mg toremifene daily are being tested and studies use up to 100 mg droloxifene daily. Side effects appear comparable, but neither droloxifene nor toremifene produce liver tumors in rats. Tamoxifen produces DNA adducts, whereas toremifene and droloxifene appear to be only weakly active. A new tamoxifen analogue, idoxifene, is entering clinical trial. The drug is designed to be metabolically stable so that there will be low carcinogenic potential. In contrast, a novel strategy may be considered to be of value to protect women from developing breast cancer. It is known from laboratory and clinical studies that antiestrogens protect bone and prevent rat mammary cancer. One compound, raloxifene, is being tested as an agent to treat osteoporosis. If the drug becomes generally available to prevent osteoporosis in postmenopausal women, a beneficial side effect may be a reduction in breast cancer risk.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alternate antiestrogens and approaches to the prevention of breast cancer. 853 10

Platinum-based chemotherapy is still the cornerstone in the chemotherapeutic approach of ovarian cancer patients. Recent advances include the introduction of paclitaxel in first-line chemotherapy and the demonstrated importance of administering cisplatin intraperitoneally in patients with small-volume disease. DNA repair and apoptosis are increasingly recognized as important processes involved in resistance to chemotherapy. Tamoxifen use is associated with a higher risk of endometrial cancer, with duration and cumulative dose of tamoxifen as additional factors. Hormonal therapy continues to be an important component of treatment of patients with advanced or recurrent endometrial cancer. Combination chemotherapy induces higher response rates in such patients. However, any advantage towards an improved survival remains a controversial issue. Isotretinoin plus interferon alfa-2a for squamous cell carcinoma of the cervix is still a topic of interest. There is a great need for agents and interventions with more efficacy and more specificity for the biology of the different gynecologic malignancies.
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PMID:Chemotherapy for gynecologic malignancies. 854 92

In 1973, McGuire and Chamness (In: O'Malley BW and Means AR (ed) Receptors for Reproductive Hormones, Plenum Press) summarized their work on the estrogen receptor in animal and human breast tumors, and in so doing described a target for therapeutic intervention. At that time there were no clinically useful antiestrogens, but the subsequent development of tamoxifen for breast cancer therapy has revolutionized the approach to treatment. Long-term adjuvant tamoxifen adjuvant therapy (i.e., greater than one year) has proven efficacy to enhance the survival of breast cancer patients. In addition, because there is an associated 40% decrease in contralateral breast cancer during adjuvant tamoxifen therapy and tamoxifen maintains bone density and reduces fatal myocardial infarction, clinical trials to test the worth of tamoxifen as a preventive for breast cancer in high risk women have started in the United States, United Kingdom, and Italy. Initial concerns that long-term tamoxifen causes endometrial cancer have been placed in perspective and analyzed by a review of the literature. Tamoxifen only doubles the normal risk of detecting endometrial cancer (i.e., to 2 per 1,000 tamoxifen-treated women per year), and 80% of these cases are early stage, good prognosis disease. Annual gynecological examinations and education are essential to provide reassurance for patients. The success of tamoxifen has encouraged the development of new antiestrogens to exploit the estrogen receptor as a therapeutic target. Droloxifene and TAT-59 mimic the metabolite 4-hydroxytamoxifen in having a high affinity for the estrogen receptor (Jordan et al, J Endocrinol 75:305, 1977). These drugs appear to have a pharmacological profile similar to tamoxifen. In contrast, the new pure antiestrogens have a distinct mechanism of action and will be valuable either as a first line therapy for advanced breast cancer or as a second line endocrine therapy after the failure of long-term adjuvant tamoxifen therapy. Finally, a new strategy is being developed to exploit the target site specific action of antiestrogens. Raloxifene, an antiestrogen with high affinity for the estrogen receptor but only weak estrogenicity for the uterus, prevents rat mammary tumorigenesis and maintains bone density. The drug is to be evaluated as a treatment for osteoporosis, but may also prevent the development of breast and endometrial cancer in a broad group of treated subjects. The identification of the estrogen receptor as a target for therapeutic opportunities has proved to be extremely beneficial for the control of breast cancer and has the added potential to control osteoporosis and coronary heart disease in women.
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PMID:Third annual William L. McGuire Memorial Lecture. "Studies on the estrogen receptor in breast cancer"--20 years as a target for the treatment and prevention of cancer. 857 10

A significant increase in endometrial cancer incidence in tamoxifen-treated breast cancer patients has been reported in many recent studies. The major growth stimulators of endometrial tumors are estrogens, but paradoxically, tamoxifen, a known antiestrogen, also stimulates their growth. The mode of action of estrogen can be partially explained by the modulation of insulin-like growth factor (IGF) autocrine or paracrine action. The purpose of the present study was to examine the involvement of the IGF system in the tamoxifen-stimulated growth of Ishikawa endometrial cancer cells by quantitating the IGF-I receptors and their phosphorylation, as well as membrane associated and secreted IGF-binding proteins (IGFBPs). Tamoxifen did not affect the number or affinity of IGF-I receptors. On the other hand, tamoxifen, similar to estradiol, increased IGF-I-stimulated tyrosine phosphorylation of cellular substrates. In contrast, in MCF-7 mammary cancer cells, tamoxifen reduced IGF-induced tyrosine phosphorylation in the presence of estradiol. The pure antiestrogen LY156758 did not affect Ishikawa basal cell growth but inhibited estradiol- and tamoxifen-induced growth. Growth inhibition by LY156758 of tamoxifen and estradiol-stimulated cells was accompanied by a corresponding inhibition of IGF-stimulated tyrosine phosphorylation. Tamoxifen caused a 3-fold decrease in membrane-associated IGFBPs. Moreover, a reduction in soluble IGFBPs was also observed, making the IGF peptides more available to the receptors. A parallel decrease in IGFBP-3 mRNA was also detected. These experiments suggest that tamoxifen, like estradiol, directly sensitizes endometrial cancer cells to the effects of IGFs that act through the type I receptor. Furthermore, the decrease in IGFBPs and the increase in tyrosine phosphorylation in the presence of tamoxifen provides a molecular mechanism that accounts for the uterotropic effects that are seen with tamoxifen therapy.
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PMID:Stimulation of endometrial cancer cell growth by tamoxifen is associated with increased insulin-like growth factor (IGF)-I induced tyrosine phosphorylation and reduction in IGF binding proteins. 860 78


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