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)

Between 1983 and 1992 in greater Milan, Italy, staff at the Italian National Cancer Institute, several university hospitals, and the Ospedale Maggiore collected data on women under 75 years old with various forms of cancer. Researchers aggregated the cancer data as well as data on women with no cancer from various medical facilities to examine the effect of reproductive factors on the risks of various cancers. They controlled for age, education, use of oral contraceptives and estrogen replacement treatments, and some various reproductive factors. Parity increased the relative risk (RR) of developing liver cancer (RR for women with =or 4 births vs. nulliparae = 3.3; p .05) and of developing cervical cancer (RR = 4.1 p .01). Multiparity appeared to exert a protective effect against breast cancer (RR = .8), endometrial cancer (RR = .7), and ovarian cancer (RR = .8) (p .05 for all 3 cancers). The older the women were at 1st birth, the greater the RR of developing breast cancer (RR - 1.4 for age 25-29 and 1.5 for =or age 30 vs. 25 years; p .01). On the other hand, the RR of developing cervical cancer decreased with increasing age at 1st birth (RR = 0.7 for age 25-29 and 0.6 for =or age 30; p .05). Miscarriages exerted a significant trend only on ovarian cancer (RR = 0.7 for =or 2; p .05 for the trend), but at least 2 miscarriages also appeared to protect against endometrial cancer (RR = 0.6; p .05). Induced abortions exerted a strong protective effect against endometrial cancer (RR = .05 for at least 1 abortion; p .01 for the trend [X = 17.49]). They also had a protective effect against colon cancer (RR = 0.4 for at least 2 abortions; p .05) and breast cancer (RR = 0.8; p .05). On the other hand, induced abortions increased the RR of developing cervical cancer (RR = 1.5 for at least 1 abortion; p .01 for the trend [X = 13.61]). These findings provide a quantitative data set on the positive or negative longterm effect of reproductive factors on cancer risk.
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PMID:Long-term impact of reproductive factors on cancer risk. 842 57

Long-term tamoxifen has generally only few and usually mild adverse side effects. More serious, potentially life-threatening toxicities are rare. Aside from the ocular effects, most documented side effects appear to be related to the estrogenic properties of tamoxifen, for instance, thrombembolic disease and endometrial cancer. On the other hand, these properties may also be beneficial, for instance, they may contribute to a decreased risk of cardiac disease and osteoporosis. The potential association between tamoxifen and other possibly estrogenic side effects such as liver cancer and tamoxifen-induced tumor growth in patients with acquired tamoxifen resistance remain controversial.
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PMID:Long-term toxicity of tamoxifen. 850 24

We analyzed cancer incidence and mortality in a cohort of 22,597 Swedish women who were prescribed replacement hormones. After 13 years of follow-up in national registries, 2,330 incident cancer cases and 848 cancer deaths were observed. Overall, our results were reassuring since incidence rate ratios (SIRs) for 16 cancer sites and mortality ratios (SMRs) for all 10 examined sites were at, or lower than, unity. However, we found that exposure to an estrogen-progestin combined brand was associated with an increasing relative risk of breast cancer with follow-up time, the SIR reaching 1.4 (95% CI 1.1-1.8) after 10 years of follow-up. The relative risk of endometrial cancer was substantially increased, with the highest SIR of 5.0 (95% CI 1.6-5.9) in women prescribed estrogens alone, whereas those given an estrogen-progestin combination showed no elevation in risk. The risk estimates for liver and biliary tract cancers and for colon cancer were reduced by about 40%, notably in women prescribed the estradiol-progestin compound. Further detailed analyses revealed no evidence of adverse or protective effects on the risk of ovarian, uterine cervical, vulvar/vaginal, rectal, pancreatic, renal, lung, thyroid and other endocrine cancers, brain tumors, malignant melanoma or other skin cancers. Hormone replacement therapy was not associated with an increase in mortality for any cancer site, at this time of follow-up. For breast and endometrial cancers, SMRs were below baseline but tended to increase with follow-up time. We conclude that hormone replacement increases the endometrial-cancer risk after unopposed estrogens and the breast-cancer risk-notably after estrogen-progestin combined therapy-and tentatively suggest that it exerts a protective effect against colon and liver cancer risks.
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PMID:Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy--long-term follow-up of a Swedish cohort. 870 4

Concern for a risk of cancer in humans has been prompted by the appearance of hepatocellular carcinomas in tamoxifen-treated rats. However, there is no evidence of excess hepatocellular carcinoma among tamoxifen-treated women. Moreover, liver tumors are not induced in tamoxifen-treated mice or hamsters. An explanation for the species selectivity of this toxic effect may relate to the greater rate of formation of reactive intermediates in rats than either mice or humans. This results in persistent liver DNA adducts in tamoxifen-treated rat liver exceeding those produced in treated mice or in background levels measured in women taking tamoxifen. Another observation that reduces concern for human carcinogenesis is that bioactivation of tamoxifen may be inducible at dosages used in rodent cancer bioassays but not in those used clinically. Suggestions that endometrial cancer may be tamoxifen related are not supported by rodent data for endometrial cancer. Indeed, endometrial tissue lacks the necessary tamoxifen bioactivating capacity of liver consistent with the absence of DNA adducts in the endometrium of women taking tamoxifen. Finally, it seems doubtful that the colon is a target for human carcinogenesis of tamoxifen given the negative epidemiologic studies and high-dose rodent studies. In summary, there is at present no sound scientific basis for extrapolation of rat liver cancer findings to risks of liver, endometrial, and colon cancer in women receiving tamoxifen.
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PMID:Relevance of rat liver tumors to human hepatic and endometrial cancer. 904 9

The nonsteroidal antiestrogen tamoxifen is the most widely used anticancer drug. In women with breast cancer, adjuvant therapy with tamoxifen reduces relapse and improves overall survival. In advanced breast cancer, the response rate is more than 50% in hormonal dependent disease. In women treated with adjuvant tamoxifen the incidence of new primary breast cancers is decreased. This latter observation has led to the initiation of prevention trials. In 1989 the first report from a large prospective randomised trial showed a significant increase of endometrial carcinoma among women treated with adjuvant tamoxifen. This effect may be linked to the somewhat paradoxical estrogenic properties of tamoxifen. The endometrial effects should be considered in the long term use of tamoxifen, and should also be taken into account in the evaluation of the prevention trials. Animal data indicate that tamoxifen can induce tumours in other organ systems, for example the liver, but no increase in primary liver cancer has been reported from the randomised trials. In some of these trials an increase in other gastrointestinal cancers (e.g. colon and gastric carcinoma) has been observed. The mechanism behind this may be different from that of the endometrium. In animal systems, tamoxifen has shown to induce DNA damage, with formation of DNA adducts. The risk of secondary gastrointestinal cancer needs to be further evaluated. The adverse effects of tamoxifen have led to the development of new anti-estrogenic drugs and other estrogen reducing agents (e.g. aromatase inhibitors).
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PMID:Tamoxifen and secondary tumours. An update. 906 22

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

The antiestrogen tamoxifen is widely used in the adjuvant therapy of breast cancers in women and helps to prevent the occurrence of breast tumors in healthy women. However, epidemiological studies have shown tamoxifen treatment to be associated with a 2- to 5-fold increased risk of endometrial cancer. In rats but not in mice, long-term administration of tamoxifen results in an increase in hepatocellular carcinomas. Mechanistically, this occurs through metabolic activation of the drug, mainly by the CYP3A family, to an electrophilic species, that causes DNA damage in target tissues, and subsequently leads to gene mutations. It is controversial whether low levels of DNA damage occur in human uterine tissues, and there is no evidence that this can be causally related to the mechanisms of carcinogenesis. In healthy women, the risk:benefits for the use of tamoxifen is in part related to the risk of developing breast cancer. The results from the carcinogenicity studies in rats do not predict the likelihood that women will develop liver cancer or indeed cancers in other organs. The mechanism of endometrial cancer in women remains unresolved, but the experience with tamoxifen has highlighted the potential problems that need to be addressed in the assessment of future generations of selective estrogen receptor modulators.
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PMID:Chemoprevention of breast cancer by tamoxifen: risks and opportunities. 1105 36

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

The drug tamoxifen, used to treat breast cancer, causes liver cancer in rats and endometrial cancer in women. Tamoxifen forms liver DNA adducts in both short- and long-term dosing of rodents, and DNA adducts have also been reported in tissues of women undergoing tamoxifen therapy. It is not known if the induction of endometrial cancer in women is through these DNA adducts or through the estrogenic nature of the drug. In this study, we have investigated the mutagenicity of two model reactive intermediates of tamoxifen, alpha-acetoxytamoxifen and 4-hydroxytamoxifen quinone methide (4-OHtamQM). These form the same DNA adducts as those found in tamoxifen-treated rats. The two compounds were used to treat the pSP189 plasmid containing the supF gene, which was replicated in Ad293 cells before being screened in indicator bacteria. Plasmid reacted with 4-OHtamQM was more likely to be mutated (2-7-fold increase) than that reacted with alpha-acetoxytamoxifen, despite having a lower level of DNA damage (12-20-fold less), as assayed by (32)P-postlabeling. The two compounds induced statistically different mutation spectra in the supF gene. The majority of mutations in alpha-acetoxytamoxifen-treated plasmid were GC -->TA transversions while GC-->AT transitions were formed in 4-OHtamQM-treated plasmid. 4-OHTamQM-treated DNA induced a larger proportion of multiple mutations and large deletions compared to alpha-acetoxytamoxifen. Sites of mutational hotspots were observed for both compounds. In conclusion, the quantitatively minor DNA adduct of tamoxifen (dG-N(2)-4-hydroxytamoxifen) is more mutagenic than the major tamoxifen DNA adduct (dG-N(2)-tamoxifen).
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PMID:DNA adducts formed from 4-hydroxytamoxifen are more mutagenic than those formed by alpha-acetoxytamoxifen in a shuttle vector target gene replicated in human Ad293 cells. 1210 32

In the second part of our review we describe the association between tobacco use and risk of specific cancer types. There is evidence for an established association of tobacco use with cancer of the lung and larynx, head and neck, bladder, oesophagus, pancreas, stomach and kidney. In contrast, endometrial cancer is less common in women who smoke cigarettes. There are some data suggesting that tobacco use increases the risk for myeloid leukaemia, squamous cell sinonasal cancer, liver cancer, cervical cancer, colorectal cancer after an extended latency, childhood cancers and cancer of the gall bladder, adrenal gland and small intestine. Other forms of cancer, including breast, ovarian and prostate cancer, are unlikely to be linked to tobacco use.
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PMID:Tobacco use and cancer causation: association by tumour type. 1292 18


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