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 a liver carcinogen in rats and has been associated with an increased risk of endometrial cancer in women. Recent reports of DNA adducts in leukocyte and endometrial samples from women treated with tamoxifen suggest that it may be genotoxic to humans. One of the proposed pathways for the metabolic activation of tamoxifen involves oxidation to 4-hydroxytamoxifen, which may be further oxidized to an electrophilic quinone methide. In the present study, we compared the extent of DNA adduct formation in female Sprague-Dawley rats treated by gavage with seven daily doses of 54 micromol/kg tamoxifen or 4-hydroxytamoxifen and killed 24 h after the last dose. Liver weights and microsomal rates of ethoxyresorufin O-deethylation, 4-dimethylaminopyrine N-demethylation and p-nitrophenol oxidation were not altered by tamoxifen or 4-hydroxytamoxifen treatment. Uterine weights were decreased significantly and uterine peroxidase activity was decreased marginally in treated as compared with control rats. DNA adducts were assayed by 32P-post-labeling in combination with HPLC. Two major DNA adducts were detected in liver DNA from rats administered tamoxifen. These adducts had retention times comparable with those obtained from in vitro reactions of alpha-acetoxytamoxifen and 4-hydroxytamoxifen quinone methide with DNA. Hepatic DNA adduct levels in rats administered 4-hydroxytamoxifen did not differ from those observed in control rats. Likewise, adduct levels in uterus DNA from rats treated with tamoxifen or 4-hydroxytamoxifen were not different from those detected in control rats. These data suggest that a metabolic pathway involving 4-hydroxytamoxifen is not a major pathway in the activation of tamoxifen to a DNA-binding derivative in Sprague-Dawley rats.
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PMID:Comparison of the DNA adducts formed by tamoxifen and 4-hydroxytamoxifen in vivo. 1019 May 64

Estrogens are important for both normal cell growth and malignant proliferation in the mammary gland as well as in the endometrium. Tamoxifen is a non-steroidal anti-estrogen widely used in breast cancer treatment. In recent years reports have been made of an increased risk of endometrial carcinoma during tamoxifen treatment. We used surgically menopausal cynomolgus macaques to study proliferation and p53 expression during hormonal replacement therapy (HRT) and tamoxifen treatment. Animals were treated continuously for 35 months with either conjugated equine estrogens (CEE; n = 20); medroxyprogesterone acetate (MPA; n = 17); the combination of CEE + MPA (n = 13); or tamoxifen (n = 17) for 35 months. We found an increased expression of p53 in normal breast and endometrial tissue linked to CEE but not tamoxifen treatment. In the breast alveoli there was an association between proliferation measured by morphometry and p53 expression in all groups. However, in the endometrium CEE induced significantly more p53 positivity than tamoxifen, 9/20 vs. 3/17 in glands and 9/19 vs. 0/17 in stroma, respectively. If indeed long-term treatment with tamoxifen as in the present study could inactivate the tumor-suppressive function of p53, endometrial cells might thereby become more susceptible to genetic lesions associated with carcinogenesis.
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PMID:p53 expression in breast and endometrium during estrogen and tamoxifen treatment of surgically postmenopausal cynomolgus macaques. 1020 73

We report a case of a 43-year-old woman with the simultaneous presence of a primary uterine endometrial cancer and metastasis of breast cancer to the ovary after 5 years of tamoxifen therapy. Tamoxifen therapy lengthens recurrence-free survival of the patient. However, the risk of endometrial cancer and the possibility of recurrence of breast cancer also must be considered.
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PMID:A case of simultaneous presence of primary endometrial carcinoma and metastasis of a breast carcinoma to the ovary after 5 years of tamoxifen therapy. 1037 26

Tamoxifen is the most widely prescribed anticancer drug in the world. It not only improves overall survival and decreases recurrence from breast cancer, but has beneficial effects on bone density and lipid profiles. Unfortunately, tamoxifen carries disadvantages such as unpleasant side effects and a questionable connection to endometrial carcinoma. However, after intense debate, the general consensus among the medical community is that the benefits of tamoxifen far outweigh the risks. Nonetheless, resistance to tamoxifen has been seen both in the clinic and in the laboratory prompting investigators to look for new antiestrogens in the treatment and prevention of breast cancer. We report on three agents: toremifene (Fareston®), ICI 182, 780 (Faslodex®), and raloxifene (Evista®). Unfortunately, clinical studies comparing tamoxifen and toremifene in the treatment of breast cancer have not shown a clear advantage of toremifene over tamoxifen. ICI 182, 780 is a "pure antiestrogen" that carries a low incidence of side effects and may hold promise as an effective agent for patients who have failed tamoxifen therapy or even as primary adjuvant therapy. Raloxifene displays beneficial bone and cardiovascular effects without uterine stimulation. It is being used as an agent to prevent osteoporosis and holds promise as an agent for advanced breast cancer. We hope that these new antiestrogens will revolutionize the way we treat breast cancer.
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PMID:Questions about Tamoxifen and the Future Use of Antiestrogens. 1038 91

Women treated for breast cancer with tamoxifen are at increased risk of developing endometrial cancer. This carcinogenic effect has been attributed to estrogenic stimulation and/or to a genotoxic effect of this drug. To examine genotoxicity, we developed a (32)P-postlabeling TLCL/HPLC procedure for quantitative analysis of tamoxifen-DNA adducts in endometrial tissue. This assay is several orders of magnitude more sensitive than those previously used for this purpose; with it, we can detect five tamoxifen-DNA adducts in 10(11) bases. Endometrial tissue was obtained from women undergoing tamoxifen therapy and from untreated control subjects. DNA adducts, identified as trans and cis epimers of alpha-(N(2)-deoxyguanosinyl)tamoxifen, were detected in six of thirteen patients in the tamoxifen-treated group. Levels of trans and cis adducts ranged from 0.5 to 8.3 and from 0.4 to 4.8 adducts/10(8) nucleotides, respectively. Tamoxifen-DNA adducts were not detected in endometrial tissue obtained from the control subjects. We conclude from this study that one or more tamoxifen metabolites react with endometrial DNA to form covalent adducts, establishing the potential genotoxicity of this drug for women and suggesting the use of TAM-DNA adducts as biomarkers for investigations of tamoxifen-induced endometrial cancer.
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PMID:Tamoxifen-DNA adducts detected in the endometrium of women treated with tamoxifen. 1040 5

Breast cancer is the most frequent cancer in women while it is the second cause of cancer death. Estrogens are well recognized to play the predominant role in breast cancer development and growth and much efforts have been devoted to the blockade of estrogen formation and action. The most widely used therapy of breast cancer which has shown benefits at all stages of the disease is the use of the antiestrogen Tamoxifen. This compound, however, possesses mixed agonist and antagonist activity and major efforts have been devoted to the development of compounds having pure antiestrogenic activity in the mammary gland and endometrium. Such a compound would avoid the problem of stimulation of the endometrium and the risk of endometrial carcinoma. We have thus synthesized an orally active non-steroidal antiestrogen, EM-652 (SCH 57068) and the prodrug EM-800 (SCH57050) which are the most potent of the known antiestrogens. EM-652 is the compound having the highest affinity for the estrogen receptor, including estradiol. It has higher affinity for the ER than ICI 182780, hydroxytamoxifen, raloxifene, droloxifene and hydroxytoremifene. EM-652 has the most potent inhibitory activity on both ER alpha and ER beta compared to any of the other antiestrogens tested. An important aspect of EM-652 is that it inhibits both the AF1 and AF2 functions of both ER alpha and ER beta while the inhibitory action of hydroxytamoxifen is limited to AF2, the ligand-dependent function of the estrogen receptors. AF1 activity is constitutive, ligand-independent and is responsible for mediation of the activity of growth factors and of the ras oncogene and MAP-kinase pathway. EM-652 inhibits Ras-induced transcriptional activity of ER alpha and ER beta and blocks SRC-1-stimulated activity of the two receptors. EM-652 was also found to block the recruitment of SRC-1 at AF1 of ER beta, this ligand-independent activation of AF1 being closely related to phosphorylation of the steroid receptors by protein kinase. Most importantly, the antiestrogen hydroxytamoxifen has no inhibitory effect on the SRC-1-induced ER beta activity while the pure antiestrogen EM-652 completely abolishes this effect, thus strengthening the need to use pure antiestrogens in breast cancer therapy in order to control all known aspects of ER-regulated gene expression. In fact, the absence of blockade of AF2 by hydroxytamoxifen could explain why the benefits of tamoxifen observed up to 5 years become negative at longer time intervals and why resistance develops to tamoxifen. EM-800, the prodrug of EM-652, has been shown to prevent the development of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat, a well-recognized model of human breast cancer. It is of interest that the addition of dehydroepiandrosterone, a precursor of androgens, to EM-800, led to complete inhibition of tumor development in this model. Not only the development, but also the growth of established DMBA-induced mammary carcinoma was inhibited by treatment with EM-800. An inhibitory effect was also observed when medroxyprogesterone was added to treatment with EM-800. Uterine size was reduced to castration levels in the groups of animals treated with EM-800. An almost complete disappearance of estrogen receptors was observed in the uterus, vaginum and tumors in nude mice treated with EM-800. EM-652 was the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro when compared with ICI 182780, ICI 164384, hydroxytamoxifen, and droloxifene. Moreover, EM-652 and EM-800 have no stimulatory effect on the basal levels of cell proliferation in the absence of E2 while hydroxytamoxifen and droloxifene had a stimulatory effect on the basal growth of T-47D and ZR-75-1 cells. EM-652 was also the most potent inhibitor of the percentage of cycling cancer cells. (ABSTRACT TRUNCATED)
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PMID:EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium. 1041 81

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.
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PMID:[Selective estrogen-receptor modulators (SERM's) in postmenopausal women]. 1060 80

Selective estrogen receptor modulators (SERMs) act exclusively through estrogen receptors and possess tissue-specific agonistic or antagonistic properties. The effects of all referred SERMs in bone and cardiovascular system are estrogenic, namely they inhibit postmenopausal bone loss and favorably influence plasma lipoproteins and some coagulation factors. The aim of this paper is to review the effects of SERMs on estrogen-dependent breast tissues and on the endometrium. There are two types of SERMs in clinical use, based on their chemical structure: the triphenylethylenes and the benzothiophenes. The prototype of the SERMs with triphenylethylene structure is tamoxifen. Tamoxifen, like all other SERMs, is an estrogen antagonist in the breast and is widely used for adjuvant treatment of breast cancer. A recent study suggests that tamoxifen also may prevent breast cancer in patients at risk. Because of the partial estrogenic activity of tamoxifen in the endometrium, its clinical use is associated with uterine hypertrophy and an increased risk of endometrial cancer. Other triphenylethylene SERMs, droloxifene, toremifene, and idoxifene, also show efficacy in the treatment of breast cancer, in a manner similar to tamoxifen. A better toxicology profile and a decreased endometrial estrogen agonism may be advantages of the new triphenylethylene SERMs. Raloxifene is a SERM with a chemical structure different from triphenylethylenes. Raloxifene, a benzothiophene, possesses an estrogen-antagonistic effect in the breast similar to triphenylethylenes. Clinical studies on postmenopausal osteoporotic women on raloxifene as compared with placebo show a significant decrease in the rate of newly diagnosed breast cancers. In clinical studies, in contrast to tamoxifen, no stimulatory effect in the endometrium could be observed with raloxifene.
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PMID:[Effect of selective estrogen receptor modulators on estrogen-sensitive tissues]. 1062 80

The term "SERM" stands for "Selective Estrogen Receptor Modulators", substances which act on certain organs as oestrogen agonists and on other organs as oestrogen antagonists. They can exert the known oestrogen-like effects on bone and lipids without exerting any action on the endometrium and the breast, a potentially ideal profile for postmenopausal hormone replacement treatment. Long known are clomifen, an ovulation stimulator, and tamoxifen, used for secondary prevention in breast cancer. Tamoxifen prevents postmenopausal bone loss as efficiently as hormone replacement treatment, and lowers blood lipids and the coronary risk, but increases the risk of endometrial cancer; for this reason it cannot be used in the prevention of postmenopausal osteoporosis. Raloxifen stimulates neither the endometrium nor the mammary gland, and probably even lowers the risk of breast cancer. Its relatively mild but significant effect on BMD (+ 2-3%/2 years) is sufficient for prevention, and in osteoporotics goes along with a substantial decrease in vertebral fracture incidence (by about 50%) comparable to the effect of other treatments. As in hormone replacement treatment, thromboembolism and leg cramps occur more frequently. Therefore, raloxifen can be used in women free of climacteric symptoms for the prevention and treatment of postmenopausal osteoporosis with no increased risk of phlebitis, alone or in combination with calcium, vitamin D, bisphosphonates and calcitonin; in future it may also be useful in male osteoporosis.
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PMID:[Selective estrogen receptor modulators (SERM): new substances for hormone replacement therapy]. 1063 85

Tamoxifen is the most important anti-breast cancer drug in clinical use and has the potential to be used as a chemopreventive breast cancer agent. Using outpatient hysteroscopy and based on 2 case control and 2 cohort follow-up studies in our department, we were able to demonstrate that 50% of women receiving long term tamoxifen experienced some sort of adverse endometrial effects. Although many women retain an atrophic endometrial layer, tamoxifen intake can lead to extensive senile cystic atrophia of the human endometrium, to endometrial hyperplasia and to endometrial polyp formation. Based on a critical review of the literature, we have shown that tamoxifen doubles the risk for developing endometrial cancer in postmenopausal women, although this increased risk may be higher and is duration (i.e. time of use)-dependent. Screening patients with breast cancer for endometrial abnormalities while they are taking tamoxifen is feasible and uterine morbidity related to tamoxifen intake is preventable. Although screening may increase drug compliance it may not be cost-beneficial. However, uterine safety becomes important when only a small benefit of the treatment is to be expected as in the use of tamoxifen in healthy women for breast cancer prevention. The aim of this report is to discuss methods and guidelines for detecting endometrial adverse effects of tamoxifen and to provide the clinician with a current opinion on timing and frequency of screening patients taking tamoxifen for the development of endometrial cancer. In summary, those who advocate screening should start with pretreatment uterine assessment using transvaginal ultrasonography or outpatient hysteroscopy. Symptom-free women with a normal pretreatment uterine cavity can be screened annually with transvaginal sonography from 2 to 3 years after the start of tamoxifen. Hysteroscopy or saline infusion sonography will be required if there is endometrial thickening because the only value of transvaginal ultrasonography is a normal finding being a thin rectilinear endometrium.
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PMID:Guidelines for monitoring patients taking tamoxifen treatment. 1064 72


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