Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen is a nonsteroidal antiestrogen that has found successful applications for each stage of breast cancer in the treatment of selected patients. Tamoxifen was originally introduced for the treatment of advanced disease in postmenopausal women; however, the drug is now also available for the palliative treatment of premenopausal women with estrogen receptor (ER) positive disease. The proven efficacy of tamoxifen and the low incidence of side effects made the drug an ideal agent to test as an adjuvant therapy for women with node-positive breast cancer. Laboratory studies indicate that long-term treatment schedules may provide maximal benefit in preventing recurrence, and recent analysis of clinical trials demonstrates that between 2 and 5 years of adjuvant tamoxifen therapy provides a survival advantage for postmenopausal women with node-positive disease. Similarly, adjuvant studies in node-negative breast cancer have demonstrated an increase in the disease-free survival of both pre- and postmenopausal patients with ER-positive tumors. However, the extended use of tamoxifen has raised questions about the long-term safety of antiestrogen therapy. Of special concern is the impact of tamoxifen on ovarian function in premenopausal women and the potential risks to the fetus if pregnancy occurs. Fortunately, there are no reports about the teratogenicity of tamoxifen in the human, but it is important that physicians counsel women about the risk of pregnancy. Tamoxifen should not be used if a patient is pregnant. Initial concerns that the long-term administration of an antiestrogen would increase bone loss and increase the risks of coronary heart disease appear to be unwarranted. Tamoxifen has some estrogen-like activities in postmenopausal women and causes a preservation of bone in the lumbar spine and a decrease in circulating cholesterol. Indeed, a reduction in fatal myocardial infarction (MI) has been noted during 5 years of tamoxifen therapy, possibly the direct result of a prolonged reduction in circulating cholesterol. However, the estrogen-like qualities of tamoxifen that could be valuable as a hormone replacement therapy for all postmenopausal women following a diagnosis of breast cancer may also increase the risk for developing endometrial carcinoma. To date, there are only a few reports of endometrial carcinoma being diagnosed during adjuvant therapy with tamoxifen; however, any instances of uterine bleeding or spotting should be followed up with an endometrial biopsy. There are some concerns about large doses of tamoxifen promoting liver cancer in rats. These results are of particular concern if tamoxifen is to be used as a preventive in normal women.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of tamoxifen in the treatment and prevention of breast cancer. 158 40

Recent studies on HCC treatment reveal a tendency to use combined immuno-chemo-therapy. Additionally, new agents have been suggested in this field. We therefore studied 7 patients with proven inoperable HCC who were treated in accordance with the following protocol, and 5 untreated patients used as controls. Therapeutic trial: 1) 1FNa (Roferon): 6 MU x 7 days consecutively every 3 weeks, 2) Adriamycin (doxorubicin): 60 mg/m2 i. v. once every 3 weeks (500 mg total dose), 3) Tamoxifen: 10 mg p.o. twice daily continuously 4) Desferrioxamine (DFO): 500 mg i.m. daily x 7 days consecutively every 3 weeks, 5) ascorbic acid: 300 mg p.o. daily 1 hour after DFO administration x 7 days consecutively every 3 weeks. Follow-up studies were performed monthly and comprised clinical, biochemical, radiological and immunological (T-cell subsets, NK cells, monocyte-macrophage function, IL-2r expression, HLA-DR expression) parameters. Compared with the control group, the treated group had a longer survival rate (p < 0.001), increased tumor regression and less progressive disease. Immunologically, the treated patients with the maintenance of a sufficient immune status were associated with a prolonged survival rate. No serious side effects of the regimen were observed. In conclusion, IFNa combined with chemohormonal therapy appears to be beneficial in HCC patients. In addition, a prolonged survival rate might correlate with the maintenance of an adequate immune status in the patients.
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PMID:Recombinant a2 interferon (a-IFN) with chemo-hormonal therapy in patients with hepatocellular carcinoma (HCC). 778 31

Tamoxifen was administered in the diet (420 p.p.m.) to female F344 (Fischer), Wistar (LAC-P) and LEW (Lewis) rats to determine for each strain the early morphological and biochemical changes associated with the subsequent development of liver cancer. Hepatic DNA damage, as determined by 32P-postlabelling, showed a cumulative increase with time from 500 adducts/10(8) nucleotides at 30 days to almost 3000 adducts/10(8) nucleotides after 180 days, with little difference between strains at this time point. A significant strain difference was found in the number of adducts present in the Fischer rats at 90 days, compared to the Wistar and Lewis strains. There was a marked strain differences in the time to development of liver tumours. After 6 months treatment, both Wistar and Lewis rats had tumours while none were seen in the Fischer animals. After 11 months, all of the Wistar and Lewis rats had developed liver carcinoma, while the Fischer rats developed liver carcinoma by 20 months. Depression in cell proliferation, relative to age-matched controls, was seen in the livers of Fischer rats after six months of exposure to tamoxifen, in contrast to an increase in the Wistar and Lewis rats. This observation is consistent with the promotion of foci to tumours and the subsequent progression of tumours to carcinomas in the latter two strains. These data may assist in establishing the possible risk factors, such as extent of DNA damage and increased liver cell proliferation, to women with long-term prophylactic exposure to tamoxifen.
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PMID:DNA damage as assessed by 32P-postlabelling in three rat strains exposed to dietary tamoxifen: the relationship between cell proliferation and liver tumour formation. 778 46

Tamoxifen administered in the diet (420 ppm) to Wistar rats (TOX:P) for only 3 months caused cumulative hepatic DNA damage as assessed by 32P-postlabeling, consistent with the proposal that tamoxifen is a genotoxic carcinogen in this species. Promotion of tumor development with phenobarbital after discontinuation of dietary tamoxifen resulted in the formation of liver carcinomas after 9 months. At 12 and 20 months in this study, the majority of these rats had liver carcinomas. Rats treated with tamoxifen for 3 months but not promoted with phenobarbital also developed liver tumors over a longer period of time. These tumors were predominantly adenomas, with one carcinoma, and occurred at a lower incidence than the tumors produced by promotion with phenobarbital. Rats treated with phenobarbital alone did not develop tumors after 20 months. Tamoxifen-induced DNA adducts were relatively persistent, with only a 38% decrease 3 months after tamoxifen treatment had been discontinued. This demonstrates that, in a susceptible species (the rat), tamoxifen can cause initiation of liver cancer after only 3 months exposure. It is proposed that the persistence of such DNA adducts may account for the ability of phenobarbital to promote a high incidence of liver carcinoma, even after discontinuation of tamoxifen treatment. These data are relevant to the concern for women given prophylactic tamoxifen for long periods in that even if there is a relatively small amount of cumulative tamoxifen-induced liver DNA damage, liver tumors could be promoted by other agents, even after the cessation of tamoxifen treatment.
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PMID:Tamoxifen induces short-term cumulative DNA damage and liver tumors in rats: promotion by phenobarbital. 783 23

Oestrogen is intimately involved in the growth and development of breast cancer. Tamoxifen, a non-steroidal anti-oestrogen, not only is an effective adjuvant therapy for node positive and node negative disease, but also has several attractive pharmacological features that have enhanced interest in testing it as a preventive drug for breast cancer in high risk women. Tamoxifen is known to prevent contralateral breast cancer, but it also has significant oestrogenicity for reducing circulating cholesterol and preventing bone loss in the lumbar spine of postmenopausal women. Several clinical trials have been initiated around the world; however, there has been increasing concern about the safety of tamoxifen. Nevertheless, current reports indicate that there is little risk of developing endometrial and liver cancer, although further clinical studies must be planned. Concerns about retinal and thromboembolic problems remain anecdotal, and again additional research is essential. The prevention trials with tamoxifen are necessary to establish the worth and feasibility of a pharmacological intervention. If tamoxifen is found to be of value to prevent breast cancer in a broad population, then the future ability to predict breast cancer through molecular markers will provide the physician for the first time with a therapeutic option to treat the targeted patient.
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PMID:Risk factors and the prevention of breast cancer with tamoxifen. 801 98

Tamoxifen induces hepatocellular carcinomas in rats and is converted by rat hepatic cytochrome P450 enzymes into reactive metabolites capable of forming adducts with nucleic acids, proteins and chromosomal aberrations. In rats tamoxifen has also been shown to induce liver cytochrome P450 enzymes, to stimulate its own metabolism leading to greater covalent binding and to induce a higher degree of unscheduled DNA synthesis. This suggests that, at least in the rat, a sensitive species, tamoxifen may contribute significantly to its genotoxic and carcinogenic potential, by assisting its own metabolic activation. We have now investigated the effect of feeding tamoxifen to male and female Rhesus monkeys. A marked induction of the hepatic cytochrome(s) P450 is found in the monkey but, in spite of this, the in vitro metabolism of 7-ethoxyresorufin by microsomes from treated animals is markedly inhibited and so is the dealkylation of two other 7-alkoxyresorufin substrates. Evidence is presented for the accumulation in the liver of monkeys treated with tamoxifen of a powerful inhibitor of drug metabolism, and the inhibitor is identified as a metabolite of tamoxifen, its N,N-didesmethyl derivative. The level of 32P-postlabelled DNA adducts was considerably higher in rats given tamoxifen than in similarly treated monkeys. Also, whereas rats responded to tamoxifen treatment with a marked increase in covalent binding to microsomal protein, in the monkeys, where accumulation of the inhibitory metabolite in the microsomal fraction was also seen, covalent binding was not greater with microsomes from treated animals than in the corresponding controls. N,N-Didesmethyl-tamoxifen, added in vitro to human and rat microsomes, reduced significantly the extent of covalent binding, suggesting that the accumulation of the metabolite observed in the liver of primates may discourage the cytochrome P450-dependent conversion of tamoxifen into reactive derivatives and in this way protect against the formation of adducts. This mechanism may also contribute to protecting the primate against tamoxifen- induced liver cancer.
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PMID:Effect of tamoxifen feeding on metabolic activation of tamoxifen by the liver of the rhesus monkey: does liver accumulation of inhibitory metabolites protect from tamoxifen-dependent genotoxicity and cancer? 876 27

Tamoxifen, an important drug in breast cancer treatment, causes liver cancer in rats. The standard range of in vitro tests have failed to show that it causes DNA damage, but 32P-postlabelling and DNA-binding studies have shown that tamoxifen forms DNA adducts in rat liver. In 1995 a transgenic rat (Big Blue; Stratagene, La Jolla, CA) became available which harbours the bacterial lacI gene, thereby allowing the in vivo study of tamoxifen mutagenesis. Recently, we [Styles JA et al. (1996): Toxicologist 30; 161] showed that tamoxifen caused on increase in the mutation frequency at the lacI gene in these transgenic rats. In this study, we report on our preliminary analysis of the mutational spectra of 33 control and 38 tamoxifen-induced mutant lacI genes. Plasmid DNA containing the lacI gene was isolated from the mutant phages and its DNA sequence determined. In the control animal group, 81% of the mutant lacI genes were point mutations, whilst in the tamoxifen-treated group, 62% of the mutant lacI genes were point mutations. Of the tamoxifen-induced mutants, 43% were GC-->TA transversions and 70% of point mutations. In the control group, GC-->TA transversions were 19% of all mutations and 24% of point mutations. Thus, compared with control animals, tamoxifen treatment had significantly increased the proportion of GC-->TA transversions.
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PMID:Mutational spectra of tamoxifen-induced mutations in the livers of lacI transgenic rats. 899 Oct 74

Tamoxifen is being evaluated in clinical trials as a preventive agent in women at high risk for breast cancer. This new, potentially long-term therapeutic role has generated some concerns regarding safety, based on the results of animal studies that demonstrated an increased incidence of liver cancer in rats and the formation of DNA adducts. However, direct extrapolation of data from rats to risk estimates in women does not appear to be appropriate. Studies have shown that there are substantial species-related differences in activation and detoxication of tamoxifen that directly affect the formation of DNA adducts. This major species difference in DNA adduct formation appears to be the result of differences in metabolic activation and detoxication; humans form much less of the electrophilic metabolites that bind to DNA and rapidly detoxify those that are formed.
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PMID:Clinical relevance of laboratory and animal data on tamoxifen. 906 26

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

Indole-3-carbinol (I3C), a compound found in Brassica vegetables has been widely studied for its chemopreventive properties. I3C has been shown to block tumor initiation and promotion; however, it also acts as a tumor promoter. I3C and some of its acid condensation products, particularly 3,3'-diindolylmethane (I33'), have exhibited antiestrogenic properties. We report that I33' acts as an estrogen in the rainbow trout liver in vitro and in vivo by inducing vitellogenin (Vg), a well-characterized biomarker for estrogens. Precision-cut liver slices from male rainbow trout, Oncorhynchus mykiss, were incubated at 14 degrees C for 96 h in media containing I3C, I33', or a mixture of I3C acid condensation products (RXN) (0-250 microM). I33' and RXN increased Vg levels in rainbow trout liver slices by over 300- and 20-fold, respectively, vs vehicle. The efficacy of I33' induction of Vg was comparable to 17 beta-estradiol (E(2)) with 2500-fold less potency. I33' and E(2) cotreatment resulted in additive Vg induction. Tamoxifen completely inhibited I33'-induced Vg induction, suggesting that Vg induction by I33' is entirely through the estrogen receptor. In vivo, juvenile male rainbow trout were fed I3C, RXN (0-2000 mg/kg), or I33' (0-250 mg/kg) for 2 weeks. At 2000 mg/kg, I3C induced Vg by over 100,000-fold compared to controls, which was comparable to 5 mg/kg 17 beta-estradiol (the dose resulting in maximum induction). I33' was five times as potent as I3C with equal efficacy. The potency of RXN was only 5% of I3C. Again, I33' and E(2) cotreatment resulted in additive Vg induction. I33' may have accounted for Vg increases observed in trout fed I3C as it is present in liver after oral dosing at concentrations (70 microM) expected to maximally induce Vg. In trout, results in vitro and in vivo document that I33' is estrogenic, consistent with our hypothesis that I3C promotes liver cancer in trout by estrogenic pathways.
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PMID:3,3'-diindolylmethane, a major condensation product of indole-3-carbinol, is a potent estrogen in the rainbow trout. 1116 84


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