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)

Genetic alterations of tumour suppressor genes, for which loss of heterozygosity (LOH) is one mechanism of gene inactivation, are important steps in the development of endometrial cancer. To investigate the clinical relevance of LOH of BRCA1 (17q21), TP53 (17p13) and TCRD (14q11) in endometrial cancer, polymerase chain reaction (PCR)-based fluorescent DNA technology for the detection of microsatellite polymorphisms was applied. One hundred and thirteen archival endometrial cancer samples with matched normal tissues were examined. Allele loss at three loci were correlated with age, tumour size, lymph node status, metastases, stage, histological types, grade, expression of oestrogen receptor (ER) and progesterone receptor (PgR), family history of cancer, previous history of cancer or precursor lesions, and previous history of hormone replacement therapy (HRT). LOH for BRCA1 was detected in 18.1%, of TP53 in 26.9%, and of TCRD in 26.3% of informative cases. LOH of BRCA1 correlated with medium grade, positive ER status, and family history of cancer; LOH of TP53 correlated with younger age, high grade, positive PgR status, and with tumours from patients without HRT; LOH of TCRD correlated only with family history of cancer. LOH at all three loci correlated only with grade and positive family history. Allele loss of one of the three tumour suppressor loci did not correlate with disease-free survival (DFS), but LOH of BRCA1 correlated significantly with decreased overall survival (OS). The latter, together with the correlation of LOH of BRCA1 locus with steroid hormone receptor expression, might give a hint to the potential involvement of the co-localised 17 beta-hydroxysteroid dehydrogenase (HSD) gene in the development of endometrial cancer.
 ...
PMID:Loss of heterozygosity of BRCA1, TP53 and TCRD markers analysed in sporadic endometrial cancer. 989 67

Selective oestrogen receptor modulators (SERMs) constitute a group of new drugs which mimic oestrogen in some organs and tissues but have an oestrogen antagonistic mode of action in other tissues. In postmenopausal women these compounds have a favourable effect on lipoprotein cholesterol levels in the blood and bone mineral density, thereby reducing fracture risk, especially in the vertebral column. In contrast to oestrogen therapy SERMs reduce the risk of mammary carcinoma. Currently tamoxifen and raloxifene are the best known SERMs. Tamoxifen increases endometrial hyperplasia and the risk of endometrial carcinoma. Raloxifene inhibits uterine tissue proliferation and does not appear to influence the endometrium directly. Raloxifene appears to be finding a place for itself in the treatment and prevention of osteoporosis in postmenopausal women. At this moment it is not yet possible to foresee what the impact of SERMs will be in the treatment and prevention of cardiovascular diseases and breast cancer.
 ...
PMID:[Selective estrogen-receptor modulators (SERM's) in postmenopausal women]. 1060 80

Tamoxifen was administered orally to neonatal rats on days 2-5 after birth and the subsequent effects on the uterus were characterized, morphometrically, over the following 12 months. Tamoxifen inhibited development of the uterus and glands in the endometrium, indicating a classical oestrogen antagonist action. Between 24 and 35 months after tamoxifen treatment there was a significant increase in the incidence (26%) of uterine adenocarcinomas and a 9% incidence of squamous cell carcinomas of the vagina/cervix in the absence of any oestrogen agonist effect in the uterus. This demonstrates that an oestrogen agonist effect is not an absolute requirement for the carcinogenic effect of tamoxifen in the reproductive tract of the rat. The unopposed oestrogen agonist effect of tamoxifen on the endometrium may not be the only factor involved in the development of endometrial cancers. It is possible that tamoxifen causes these tumours via a genotoxic mechanism similar to that seen in rat liver. However, using (32)P-post-labelling we failed to find evidence of tamoxifen-induced DNA adducts in the uterus. Tamoxifen may affect hormonal imprinting of oestrogen receptor responses in stem cells of the uterus, causing reproductive tract cancers to arise at a later time, in the same way as has been proposed for diethylstilbestrol. If these rodent data extrapolate to humans, then women who are taking tamoxifen as a chemopreventative may have an increased risk of vaginal/cervical cancer, as well as endometrial cancer.
 ...
PMID:Tamoxifen induces endometrial and vaginal cancer in rats in the absence of endometrial hyperplasia. 1075 17

Antioestrogen therapy is currently receiving renewed interest for several reasons. Tamoxifen was introduced in the treatment of metastatic breast cancer more than three decades ago. The drug significantly reduces long term mortality and also reduces the risk of contralateral tumours when administered in early breast cancer. Five years of tamoxifen is now standard in adjuvant endocrine therapy, and the drug is currently being evaluated for breast cancer prevention. Despite this, several aspects regarding the pharmacology of the drug are still unclear, and the scientific rationale for dose selection has recently been challenged. Several novel antioestrogen compounds, called selective oestrogen receptor modifiers (SERMs), express selective oestrogen agonistic or antagonistic properties depending on the organ or test system evaluated. Some of these drugs, like raloxifene, do not seem to promote the development of endometrial cancer, although they still have selected oestrogen-like beneficial effects. This paper reviews the pharmacologic and the pharmacokinetic aspects of the different SERMs with particular emphasis on their potential use in therapy and prevention of breast cancer.
 ...
PMID:Selective oestrogen receptor modifiers (SERMs) and breast cancer therapy. 1081 62

Selective oestrogen receptor modulators (SERMs) are structurally diverse non-steroidal compounds that bind to oestrogen receptors and produce oestrogen agonist effects in some tissues and oestrogen antagonist effects in others. SERMs are being evaluated for a number of oestrogen-related diseases, including post-menopausal osteoporosis, hormone-dependent cancers, and cardiovascular disease. Several compounds that exhibit a SERM profile are currently available for clinical use, including clomiphene, tamoxifen, and toremifene (which are triphenylethylenes) and raloxifene (a benzothiophene). Clomiphene is used for the induction of ovulation in sub-fertile women attempting pregnancy. Tamoxifen and toremifene are both used to treat breast cancer. Tamoxifen may have beneficial effects on bone mineral density and serum lipids. The effects of toremifene on serum lipids are similar to that of tamoxifen. Both compounds have stimulatory effects on the endometrium. Raloxifene, indicated for the treatment and prevention of post-menopausal osteoporosis, has beneficial effects on bone mineral density and serum lipids, but does not increase the risk of endometrial hyperplasia or endometrial cancer. Recently, raloxifene was shown to reduce the incidence of vertebral fractures in otherwise healthy women with osteoporosis; in the same study, a reduced incidence of breast cancer was also observed. Similar to oestrogens, SERMs increase the incidence of venous thromboembolism. Several newer compounds that exhibit a SERM profile are also in clinical development, including other triphenylethylenes (droloxifene, idoxifene) and benzothiophenes (LY353381.HCl), benzopyrans (EM-800), and naphthalenes (CP-336,156).
 ...
PMID:A pharmacological review of selective oestrogen receptor modulators. 1087 66

The ideal selective oestrogen receptor modulator (SERM) would retain an oestrogen-like effect on the bones, the heart and cardiovascular apparatus, and the central nervous system, while acting as an anti-oestrogen on the breast and the genital tract. It seems, however, that such a compound is not available for clinical use yet. The uterine tissue, and particularly the endometrium, defines an area of special interest in the SERM action, since endometrial hyperplasia and cancer has been linked to agonistic oestrogen effects. Additionally, tamoxifen, the SERM which accumulates most of the clinical experience, has been associated with stimulatory effects on endometrium, including the development of cancer. In contrast, the more recent benzothiophenes, led by raloxifene, seem to operate as endometrial antagonists, thus providing an interesting alternative for clinical use. This review analyses the endometrial action of tamoxifen, including the information gathered from laboratory models, the observed endometrial effects in women using tamoxifen, and the epidemiological and molecular data which link the use of tamoxifen with endometrial cancer. A parallel examination of the raloxifene data presents the available experimental and clinical information, suggesting the endometrial neutrality of this compound.
 ...
PMID:The endometrial effects of SERMs. 1087 69

We assessed the relative expression of oestrogen receptor (ER)alpha and oestrogen receptor (ER)beta mRNAs in 36 human endometrial cancers using a multiplex polymerase chain reaction (PCR). To determine whether or not the expression of ER subtypes in endometrial cancers is associated with clinicopathological parameters, we examined correlations between ER subtypes and age, tumour grade and depth of myometrial invasion. Using multiple regression analysis, myometrial invasion showed a significant correlation with ER-beta: ER-alpha ratio (r = 0.54, P = 0.0007). The ER-beta:ER-alpha ratio was high in advanced invasive carcinoma. Western blotting analysis showed that ER-beta proteins were highly expressed in comparison with ER-alpha proteins in endometrial cancer with severe myometrial invasion. Our results suggest that ER-beta is important in the progression of myometrial invasion.
 ...
PMID:Oestrogen receptor beta expression and depth of myometrial invasion in human endometrial cancer. 1120 52

Selective oestrogen receptor modulators (SERMs) are compounds that act as oestrogen agonists on selected targets while being oestrogen antagonists on others. The main targets of SERMs are oestrogen agonist activity on bone metabolism and several functions of the cardiovascular system, as well as oestrogen antagonism in the breast and uterus. They are indicated for the treatment and/or prevention of breast and endometrial cancer, osteoporosis and coronary heart disease. The extensive documentation of the multiple oestrogen effects on the CNS, greater understanding of the mechanisms of action, and especially the discovery of a second oestrogen receptor with differentiated distribution and mechanisms, have all led the way to the possibility of specific CNS-targeted SERMs. The demonstration that oestrogen selectively improves cognition, delays the appearance of Alzheimer's dementia, improves the feeling of well-being, as well as the response to antidepressant medications, provides targeted CNS indications for SERMs. The CNS effects of the currently marketed SERMs are not sufficiently explored yet. However, in postmenopausal women, tamoxifen and raloxifene probably show the most oestrogen agonist CNS effects. In women of reproductive age, competition with oestrogen probably exists, resulting in antagonist effects. Activity in men is still mostly unknown. It is quite safe to predict that the recent accumulation of knowledge, combined with the large, thirsty anticipated market for these 'designer oestrogens', will lead to clinical trials of CNS-targeted SERMs in the very near future.
 ...
PMID:Selective oestrogen receptor modulators--current and future brain and behaviour applications. 1124 72

Tamoxifen is one of the most effective drugs to be used in the treatment of women with breast cancer and as a chemopreventive agent in women 'at risk' from this disease. Tamoxifen can be regarded as a paradigm for a new range of selective oestrogen receptor modulators that include toremifene, used in the treatment of metastatic breast cancer and raloxifene, presently approved for use in postmenopausal women for the treatment of osteoporosis. Tamoxifen treatment of women leads to a small increase in the incidence of endometrial cancers. It is important to understand the mechanism for this side effect in order to predict the likely human risk for other drugs of this class. Two such mechanisms have been proposed: (1) conversion of the drug to electrophilic metabolites that damage cellular DNA; and (2) an oestrogen agonist action on the uterus, promoting endogenous lesions. In rats, long-term tamoxifen treatment results in liver cancer via a genotoxic mechanism. However, it seems most likely that, in women treated with tamoxifen, endometrial cancer is related to an oestrogen agonist effect of this drug, promoting uterine cell proliferation.
 ...
PMID:Anti-oestrogenic drugs and endometrial cancers. 1132 58

Selective oestrogen receptor modulators (SERMs) are compounds that interact with the oestrogen receptor and have tissue-specific effects distinct from those of oestradiol, acting as an oestrogen agonist in some tissues and as an antagonist in others. The development of SERMs that selectively interact with specific receptors, coactivators and corepressors in different organ systems offers the possibility of improving the risk:benefit profile relative to hormone replacement therapy. Tamoxifen is a SERM that acts as an oestrogen antagonist in breast tissue and is currently being used for the treatment and prevention of breast cancer. Tamoxifen also exhibits oestrogen-agonistic properties in the endometrium and increases the risk of endometrial cancer. Oestrogen and another SERM, raloxifene, have been shown to prevent osteoporosis. The effects of oestrogens on cognitive functions are currently being investigated. Recent data reveal the lack of secondary prevention of coronary heart disease with oestrogen. Oestrogen has been used to treat menopausal symptoms, whereas the SERMs have been shown to induce hot flushes. Current research is focused on producing the ideal SERM, which would have benefits over existing SERMs in terms of preventing cancer, cardiovascular disease, osteoporosis and menopausal symptoms, improving cognitive functions, and have a significantly better toxicity profile in terms of endometrial cancer and thromboembolic events.
 ...
PMID:The search for the ideal SERM. 1203 7


<< Previous 1 2 3 4 5 Next >>