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)

Tamoxifen is widely prescribed for the treatment of hormone-dependent breast cancer, and it has recently been approved by the Food and Drug Administration for the chemoprevention of this disease. However, long-term usage of tamoxifen has been linked to increased risk of developing endometrial cancer in women. One of the suggested pathways leading to the potential toxicity of tamoxifen involves its oxidative metabolism to 4-hydroxytamoxifen, which may be further oxidized to an electrophilic quinone methide. The resulting quinone methide has the potential to alkylate DNA and may initiate the carcinogenic process. To further probe the chemical reactivity and toxicity of such an electrophilic species, we have prepared the 4-hydroxytamoxifen quinone methide chemically and enzymatically, examined its reactivity under physiological conditions, and quantified its reactivity with GSH. Interestingly, this quinone methide is unusually stable; its half-life under physiological conditions is approximately 3 h, and its half-life in the presence of GSH is approximately 4 min. The reaction between 4-hydroxytamoxifen quinone methide and GSH appears to be a reversible process because the quinone methide GSH conjugates slowly decompose over time, regenerating the quinone methide as indicated by LC/MS/MS data. The tamoxifen GSH conjugates were detected in microsomal incubations with 4-hydroxytamoxifen; however, none were observed in breast cancer cell lines (MCF-7) perhaps because very little quinone methides is formed. Toremifene, which is a chlorinated analogue of tamoxifen, undergoes similar oxidative metabolism to give 4-hydroxytoremifene, which is further oxidized to the corresponding quinone methide. The toremifene quinone methide has a half-life of approximately 1 h under physiological conditions, and its rate of reaction in the presence of excess GSH is approximately 6 min. More detailed analyses have indicated that the 4-hydroxytoremifene quinone methide reacts with two molecules of GSH and loses chlorine to give the corresponding di-GSH conjugates. The reaction mechanism likely involves an episulfonium ion intermediate which may contribute to the potential cytotoxic effects of toremifene. Similar to what was observed with 4-hydroxytamoxifen, 4-hydroxytoremifene was metabolized to di-GSH conjugates in microsomal incubations at about 3 times the rate of 4-hydroxytamoxifen, although no conjugates were detected with MCF-7 cells. Finally, these data suggest that quinone methide formation may not make a significant contribution to the cytotoxic and genotoxic effects of tamoxifen and toremifene.
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PMID:4-Hydroxylated metabolites of the antiestrogens tamoxifen and toremifene are metabolized to unusually stable quinone methides. 1064 66

Estrogens play a central role in reproductive physiology. The cellular effects of estrogens are mediated by binding to nuclear receptors (ER) which activate transcription of genes involved in cellular growth control. At least two such receptors, designated ERalpha and ERbeta, mediate these effects in conjunction with a number of coactivators. These receptors can directly interact with other members of the steroid receptor superfamily. A complex cross-talk exists between the estrogen-signaling pathways and the downstream signaling events initiated by growth factors, such as epidermal growth factor and insulin-like growth factors. Estrogens are also a causative factor in the pathogenesis of a variety of neoplastic and non-neoplastic diseases, including breast cancer, endometrial cancer, endometriosis, and uterine fibroids, among others. Antiestrogens, such as tamoxifen, are widely used for the treatment of breast cancer. Tamoxifen produces objective tumor shrinkage in advanced breast cancer, reduces the risk of relapse in women treated for invasive breast cancer, and prevents breast cancer in high-risk women. Although, initially developed as an antiestrogen, tamoxifen can also prevent postmenopausal osteoporosis as well as reduce cholesterol, due to its estrogen-agonist effects. Its estrogen-agonist activity, however, can lead to significant side-effects such as endometrial cancer and thromboembolic phenomena. This has led to the concept of "ideal" selective estrogen receptor modulators (SERMs), drugs that would have the desired, tissue selective, estrogen-agonist or -antagonist effects. Raloxifene is a SERM which has the desirable mixed agonist/antagonist effects of tamoxifen but does not cause uterine stimulation. "Pure" antiestrogens may provide very potent estrogen-antagonist drugs, but are likely to be devoid of beneficial effects on bone and lipids. Future drug development efforts should focus on developing superior SERMs that have a greater efficacy against ER-positive tumors and do not cause hot flashes or thromboembolism, and explore combination strategies to simultaneously target hormone-dependent as well as hormone-independent breast cancer.
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PMID:Antiestrogens--tamoxifen, SERMs and beyond. 1066 80

Tamoxifen is hepatocarcinogenic in rats and has been associated with an increased risk of endometrial cancer in women. Recent reports suggest that it may be genotoxic in humans. N-Desmethyltamoxifen is a major tamoxifen metabolite that has been proposed to be responsible for one of the major adducts detected in liver DNA of rats treated with tamoxifen. The metabolic activation of N-desmethyltamoxifen to DNA binding products may involve oxidation to alpha-hydroxy-N-desmethyltamoxifen followed by esterification. In the study presented here, we report the synthesis of alpha-hydroxy-N-desmethyltamoxifen and the characterization of the major adduct obtained from alpha-sulfoxy-N-desmethyltamoxifen in vitro as (E)-alpha-(deoxyguanosin-N(2)-yl)-N-desmethyltamoxifen. In addition, we use (32)P-postlabeling in combination with HPLC to compare the adducts formed in the livers of female Sprague-Dawley rats treated by gavage with tamoxifen or equimolar doses of alpha-hydroxy-N-desmethyltamoxifen. We conclude that one of the major adducts formed in vivo and previously suggested to derive from N-desmethyltamoxifen is chromatographically identical to alpha-(deoxyguanosin-N(2)-yl)-N-desmethyltamoxifen.
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PMID:Characterization of the major DNA adduct formed by alpha-hydroxy-N-desmethyltamoxifen in vitro and in vivo. 1072 17

We wanted to assess the effect of tamoxifen treated women with breast cancer, as well as to examine patients with diabetes blood hypertension, and obesity. The influence of Tamoxifen was searched over the endometrium in patients treated with it for 3 years. In this research work is assessed the effect of this medicament from this risk group. The second risk group were the women with high blood pressure, obesity and diabetes mellitus. We used transvaginal sonography and the progesterone test to find endometrial pathology and especially endometrial cancer in asymptomatic women-measuring the depth of the endometrium, and using abrasio probatoria separata in order to find endometrial cancer. With these tests we found polyps, hyperplasia, and early endometrial cancer. We wanted with progesteron test and vaginal sonography in these risk groups to find endometrial pathology and especially early endometrial cancer in asymptomatic women.
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PMID:[The progesterone test and transvaginal sonography as methods for the early discovery and screening of endometrial cancer in women in the postmenopause from some risk groups]. 1073 Mar 82

Selective estrogen receptor modulators (SERMs) appear to reduce the incidence of breast cancer in high-risk women. Five years of tamoxifen administration after the diagnosis of breast cancer results in a 50% reduction in the incidence of contralateral breast cancer. This reduction is maintained for 5 years after therapy is discontinued. The Study of Tamoxifen And Raloxifene (STAR), presently ongoing, will address the questions of breast cancer prevention, risk of endometrial cancer, the incidence of bone fractures, and coronary artery disease in women treated with these SERMs.
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PMID:Antiestrogens: clinical applications of pharmacology. 1073 29

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.
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PMID:Tamoxifen induces endometrial and vaginal cancer in rats in the absence of endometrial hyperplasia. 1075 17

Tamoxifen (TAM) is used for the adjuvant treatment of women with breast cancer and has also been recommended as a chemopreventive agent. Among unwanted side effects, TAM was shown to increase endometrial cancer in treated women by mechanisms that are not yet clearly understood. We studied DNA adducts in lymphocytes of female breast cancer patients treated with TAM or toremifene (TOR), a TAM analogue and compared them with adducts formed by TAM in rat liver, where the drug induces tumours. DNA adducts were measured by TLC-(32)P-post-labelling assays. After TLC, all DNA samples including DNA from untreated healthy women showed a faint radioactive zone, where the positive control DNA adducts isolated from the liver of rats treated with TAM migrated. The relative adduct levels were calculated from the radioactivity present in this zone. Means +/- SD of adduct levels per 10(8) nucleotides (associated with this area) were for untreated volunteers (control) 1.83 +/- 1.41 (n = 13), for TAM treatment 2.17 +/- 3.04 (n = 25) and for TOR treatment 1.18 +/- 1.05 (n = 8). Most of the human samples were further analysed by HPLC after labelling with (32)P in order to compare adducts in human DNA with those in liver DNA isolated from TAM-treated rats. None of the human samples showed any peaks at retention times where putative TAM-DNA adducts were eluted. In conclusion, lymphocyte DNA from female patients treated at therapeutic levels did not show evidence of the formation of TAM- or TOR-DNA adducts.
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PMID:Lack of evidence for tamoxifen- and toremifene-DNA adducts in lymphocytes of treated patients. 1075 26

Tamoxifen is commonly used in the management of patients with breast cancer. Clinical trials of tamoxifen involving over 75,000 patients demonstrate an improved recurrence-free and overall survival benefit in both pre- and post-menopausal women. Large-scale trials also are evaluating the role of tamoxifen as a chemopreventive agent in women considered to be at high risk for developing breast cancer based on family history. Endometrial cancer is an uncommon complication of tamoxifen therapy. Since the majority of these cancers will be detected at an early stage when they are highly curable, however, the overall benefit of tamoxifen treatment in breast cancer patients outweighs this risk. All women receiving tamoxifen who have a uterus should undergo regular gynecologic examinations.
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PMID:Tamoxifen and Endometrial Cancer. 1079 70

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.
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PMID:Selective oestrogen receptor modifiers (SERMs) and breast cancer therapy. 1081 62

Tamoxifen has been used for the treatment of breast cancer since the 1970s, but is considered a carcinogen because it has been linked to liver cancer in rats and an increased risk of endometrial cancer in patients. In rats, DNA adducts appear to be responsible for carcinogenesis, but their contribution to carcinogenesis in humans is not clear. FC-1271a and toremifene are mixed antiestrogens similar to tamoxifen. In order to compare the genotoxicity of these different triphenylethylenes, we treated mice for 28 days with 50 mg/kg of either tamoxifen, toremifene, FC- 1271 a or vehicle control. DNA from liver and uterus was assayed by standard 32P-postlabeling and thin layer chromatography for the presence of DNA adducts. Two methods of drug administration (oral and subcutaneous) and two strains of mice were compared and the plasma and tissue concentrations of the drugs and three metabolites of tamoxifen and toremifene were determined. Regardless of the conditions, only tamoxifen-treated mice showed DNA adducts in the liver. Adduct levels did not correlate with drug or metabolite levels and adducts were present even when drug was not detectable. Mice were also treated orally with either 50, 100, or 200 mg/kg of drug for 7 days. Again, adducts were found only in liver tissue of mice treated with tamoxifen, and adduct levels were dose-dependent. In conclusion, the chlorinated triphenylethylene FC-1271a did not cause DNA adducts under various conditions in mice, suggesting a low carcinogenic potential.
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PMID:Genotoxic effects of the novel mixed antiestrogen FC-1271a in comparison to tamoxifen and toremifene. 1084 10


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