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)

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).
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PMID:A pharmacological review of selective oestrogen receptor modulators. 1087 66

Tamoxifen is a nonsteroidal antiestrogen that has become the frontline endocrine therapy for all stages of breast cancer. The drug is the only single-agent therapy that, when used in an adjuvant fashion, produces a survival advantage in postmenopausal women. Survival is longer when the estrogen receptor content of the primary tumor is higher, although receptor-poor patients still have a survival advantage from adjuvant tamoxifen equivalent to that noted with combination chemotherapy. The added advantages of tamoxifen are a maintenance of bone density and a decrease in fatal myocardial infarction. Although side effects from tamoxifen are few, patients must be examined for preexisting endometrial carcinoma before beginning drug use. Tamoxifen does not prevent the growth of endometrial tumors. Spotting and vaginal bleeding in postmenopausal patients taking tamoxifen should be followed up with a thorough gynecological examination. The incidence rate of endometrial cancer for tamoxifen-treated patients is 2 per 1000 patients per year. More than 80% of detected endometrial tumors are stage 1 disease and can be cured by hysterectomy.
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PMID:Long-term Tamoxifen Therapy for the Treatment of Breast Cancer. 1088 88

The rationale for clinical trials of antiestrogens for prevention of breast cancer, potential concerns with antiestrogens, and clinical trials of antiestrogens for breast cancer prevention are discussed. Extensive preclinical evidence supports clinical investigation and use of tamoxifen for preventing breast cancer. The efficacy of tamoxifen in the treatment of advanced breast cancer and as adjuvant therapy has further strengthened the rationale for use in prevention. Tamoxifen is well tolerated and, like raloxifene, has been associated with non-cancer-related benefits. The major concerns with tamoxifen are an increased risk of thromboembolic events and endometrial cancer and an association with ocular disorders. Little is known about the long-term safety of raloxifene. Three randomized, double-blind, placebo-controlled clinical trials of tamoxifen 20 mg (as the citrate) daily for the prevention of breast cancer and one post hoc analysis and a literature review examining the effect of raloxifene on breast cancer risk (as a secondary endpoint) have been published. In one of the three trials of tamoxifen, the rate of invasive breast cancer was reduced 49%; in the other two trials, no reduction in breast cancer was found. Raloxifene apparently reduced the frequency of breast cancer. On the basis of the positive tamoxifen trial, tamoxifen can be offered to women with a five-year projected risk of breast cancer of > or = 1.67%, as determined by the Gail model. Risks and benefits should be evaluated for each patient. Tamoxifen may offer some women protection against breast cancer. Raloxifene may also have a preventive role, but more study is needed.
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PMID:Safety and efficacy of antiestrogens for prevention of breast cancer. 1091 21

Tamoxifen is the endocrine treatment of choice for all stages of estrogen receptor (ER)-positive breast cancer, and it is the first drug approved to reduce the incidence of breast cancer in high-risk women. Unfortunately, tamoxifen also possesses some estrogen-like effects in the uterus that cause a modest increase in the risk of endometrial cancer. GW5638 is a tamoxifen derivative with a novel carboxylic acid side chain with no uterotropic activity in the rat (Willson et al., J Med Chem, 1994, 37:1550-1552). We have compared and contrasted the actions of 4-hydroxytamoxifen (4-OHT, the active metabolite of tamoxifen) with GW7604 [the presumed metabolite of GW5638 in breast (MCF-7) and endometrial (ECC-1) cell lines in vitro]. GW7604 did not cause the growth of ECC-1 cells at any concentration (10(-11)-10(-6) M), but 4-OHT was weakly estrogen-like at low concentrations (10(-11)-10(-10) M). Compounds (10(-7) M) blocked the growth promoting action of estradiol (10(-10) M) in both ECC-1 and MCF-7 cells. Western blotting was used to show that GW7604 and raloxifene did not affect ER levels significantly, compared with controls, in MCF-7 cells; whereas the pure antiestrogen ICI182,780 decreased ER levels (P < 0.05). An assay system was used that can classify compounds into tamoxifen-like, raloxifene-like, or pure antiestrogens. The assay depends on the activation of the transforming growth factor alpha (TGFalpha) gene in situ by wild-type or D351Y mutant ER stably transfected into MDA-MB-231 cells (MacGregor-Schafer et al., Cancer Res, 1999, 59:4308-4313). GW7604 inhibited both estradiol (10(-9) M) and 4-OHT (10(-8), 10(-7) M) induction of TGFalpha in a concentration related manner (10(-9)-10(-6) M). GW7604 and raloxifene stimulated TGFalpha with the D351Y ER. In contrast, ICI 182,780 (10(-6) M) did not initiate TGFalpha and blocked the induction of TGFalpha with GW7604, raloxifene, and 4-OHT in D351Y-transfected cells. Using computer-assisted molecular models of ER complexes, we found that the antiestrogenic side chain of 4-OHT weakly interacted with the surface amino acid 351 (aspartate), but the carboxylic acid of GW7604 caused a strong repulsion of aspartate 351. We propose that GW7604 is less estrogen-like than 4-OHT, because it disrupts the surface charge around aa351 required for coactivator docking in the 4-OHT:ER complex. This charge is restored in the D351Y ER, thus converting GW7604 from an antiestrogen to an estrogen-like molecule.
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PMID:Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen. 1115 57

Tamoxifen (TAM) is the endocrine treatment of choice in the first-line therapy for all stages of breast cancer, in both pre- and postmenopausal women. Some clinical studies indicated a small but significant increase in the risk of subsequent endometrial carcinoma in breast cancer women who take TAM as an adjuvant therapy. In this study, we present two cases of breast cancer patients in whom endometrial cancer was diagnosed during TAM treatment; the current status of knowledge on the relationship between TAM use and the risk of endometrial cancer is reviewed.
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PMID:Endometrial cancer in patients with breast carcinoma treated with tamoxifen: report of two cases and the literature overview. 1120 46

We critically examined the literature regarding tamoxifen and raloxifene for breast cancer chemoprevention, a controversial topic of interest to all providers of health care services for women. The National Surgical Adjuvant Breast and Bowel Project showed that tamoxifen decreased the incidence of breast cancer in women at increased risk. Two European studies did not confirm this benefit. Although well-tolerated, tamoxifen chemoprevention continues to be associated with an increased risk of endometrial cancer. Raloxifene is a promising agent that has not been established to reduce the incidence of breast cancer in women at increased risk and currently should not be considered an alternative to tamoxifen outside of clinical trials. Tamoxifen results in a decreased risk of causing breast cancer in women at increased risk for having the disease. Women at increased risk are encouraged to participate in the ongoing clinical trial comparing tamoxifen and raloxifene for breast cancer prevention.
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PMID:Chemoprevention of breast cancer. 1121 47

Tamoxifen's agonist effect on the endometrium has been associated with an increased incidence of endometrial carcinoma. It has been suggested that this agonist effect may be averted by the concomitant use of a progestational agent. We report two patients with breast cancer receiving tamoxifen who developed endometrial carcinoma and atypical endometrial hyperplasia, respectively. In one patient, this occurred despite the use of concomitant megestrol acetate. In the other patient, tamoxifen-associated endometrial hyperplasia persisted and progressed despite cessation of tamoxifen and initiation of megestrol acetate therapy. These cases may have implications for strategies to avert tamoxifen induced endometrial neoplasia.
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PMID:Failure of megestrol acetate to reverse tamoxifen induced endometrial neoplasia: two case reports. 1124 Jul 94

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.
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PMID:Anti-oestrogenic drugs and endometrial cancers. 1132 58

Hormone replacement therapy (HRT) can increase the quality as well as the length of life, but a prolonged use can also increase the risk of breast cancer. The combination of HRT and a selective estrogen receptor modulator (SERM) such as tamoxifen may retain the benefits while reducing the risks of either agent. A post hoc analysis of the Italian Tamoxifen Prevention Study showed a borderline significant reduction of breast cancer among women who were on HRT continuously and tamoxifen as compared with continuous HRT users who received placebo. Recent studies suggest that the standard dose of tamoxifen may be reduced to one-quarter (i.e., 10 mg every other day) without loss of its beneficial biological effects. Since the endometrial effect of tamoxifen seems to be both dose and time dependent, a dose reduction could substantially reduce the risk of endometrial cancer while retaining its preventive efficacy. On the other hand, the addition of HRT containing progestins could also minimize the risk of endometrial cancer associated with tamoxifen. Moreover, estrogen should reduce the incidence of vasomotor and urogenital symptoms, which are a major reason for tamoxifen withdrawal in prevention studies. Notably, in the National Surgical Adjuvant Breast Project (NSABP) P-1 trial, women ages 50 or younger had no increased incidence of adverse events, including endometrial cancer and venous thromboembolic events. One possible explanation for the lack of toxicity in premenopause is the presence of adequate circulating estrogen levels which prevent tamoxifen to act as an estrogen agonist at these target tissues. Moreover, data from the current Italian tamoxifen prevention trial indicate that the compliance was substantially higher for de novo and current HRT users as compared to women who never received HRT during the study. The combination of HRT and tamoxifen at low doses could thus reduce the risks and side effects while retaining the benefits of either agent.
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PMID:Hormonal Therapy and Chemoprevention. 1134 90

Tamoxifen (TAM) is a highly effective selective estrogen receptor (ER) modulator used extensively for the treatment and prevention of breast cancer. However, prolonged treatment of women with TAM may be a risk factor for endometrial cancer, and research in our laboratory is focused on the development of selective aryl hydrocarbon receptor modulators that can be used in combination with TAM to improve its efficacy in the breast and inhibit TAM-induced endometrial effects. This study investigated the effects of the selective aryl hydrocarbon receptor modulators 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF) alone and in combination with TAM in the carcinogen-induced mammary tumor model and in the ovariectomized uterotropic assay using female Sprague Dawley rats. The lowest effective dose of 6-MCDF that inhibited tumor growth was 50 microg/kg/day, and TAM was antitumorigenic at a dose of 100 microg/kg/day. In animals cotreated with TAM + 6-MCDF at doses of 100, 50, or 25 microg/kg/day of each compound, complete inhibition of mammary tumor growth was observed at all doses, and the results are consistent with a more than additive antitumorigenic response for the low dose group (25 + 25 microg/kg) and additive interactions at the 50 and 100 microg/kg doses. In a separate experiment, 6-MCDF (800 microg/kg) inhibited TAM-induced peroxidase activity and progesterone receptor binding in the ovariectomized rat uterus but did not affect TAM-induced bone growth in ovariectomized rats. This study also investigated the effects of TAM and 6-MCDF alone and in combination on ERalpha protein levels in MCF-7 human breast cancer cells as a model for studying interactions between these compounds. The results show that 6-MCDF decreased TAM-induced ERalpha levels in the absence or presence of 17beta-estradiol through proteasome activation, and these interactions may contribute to the observed combined antitumorigenic effects of these compounds.
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PMID:Tamoxifen-induced antitumorigenic/antiestrogenic action synergized by a selective aryl hydrocarbon receptor modulator. 1135 3


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