Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen (TAM) is used in the treatment of breast cancer and is being given to healthy women to inhibit breast cancer. The present study examines the effects of TAM in female rats exposed for up to one year. Starting at 6 weeks of age, groups of 55-57 female Sprague-Dawley rats were given TAM by gavage daily at 2.8, 11.3 or 45.2 mg/kd body weight/day, for up to 1 year with two recovery segments, 4 weeks of recovery after 6 months of exposure, and 3 months of recovery after 12 months of exposure. Complete necropsies and histopathology were performed. Drug-related mortality was highest in the high TAM group. In the two high dose groups, hepatoproliferative lesions were present in time- and dose-related incidence, severity and multiplicity. In the high dose rats, at 6 months, hepatocellular adenomas and carcinomas were observed in 71 and 29% of rats respectively. With 1 month of recovery, at 7 months the adenomas and carcinomas were increased to 75%. At 12 months the adenomas were present in 50% and carcinomas in 75% of high dose rats. In the mid dose group, liver lesions were not found until 12 months; at this time 50% had adenomas and 10%, carcinomas. After a 3 month recovery period, 45% exhibited adenomas and 45%, carcinomas. Thus, TAM at 45.2 mg/kg/day elicited hepatocellular neoplasia sometime between 3 and 6 months of administration. At 11.3 mg/kg the neoplastic process was evident at 12 months. At 2.8 mg/kg, no hepatoproliferative changes were found. The strong hepatocarcinogenic effect of TAM in rats raises issues bearing on the prophylactic chronic administration to healthy women.
Carcinogenesis 1993 Feb
PMID:The triphenylethylene drug tamoxifen is a strong liver carcinogen in the rat. 843 74

Rats administered tamoxifen for 3 months and then returned to a basal diet developed an increase in uterine weight for up to 9 months after tamoxifen exposure. Stereological analysis of the tamoxifen exposed rat uteri showed that there was a significant increase in the amount of uterine myometrium, for a further 9 months, subsequent to the discontinuation of tamoxifen. A low incidence of myometrial proliferations (deciduomas) and uterine tumours was found at the conclusion of the study (20 months). In contrast, continuous administration of tamoxifen to mice for 24 months produced hyperplasia of the uterine endometrial epithelium and atrophy of the myometrium for the first 3 months, followed by atrophy of both the endometrium and myometrium for the remaining 21 months of the study. No uterine tumours were found in mice treated with tamoxifen for 2 years. The use of stereological analysis on interim sacrifice rodent uteri indicated that sustained uterine tissue compartment effects can occur, with either the continuous administration of tamoxifen, or after its discontinuation. Tamoxifen can have an agonist and antagonist like effect on oestrogen activity in different tissue compartments of the mouse uterus, over the same time period. The particular relevance of the finding of uterine proliferation and atrophy in the rodent studies with tamoxifen is discussed with regard to women taking this drug.
Carcinogenesis 1996 Aug
PMID:Tamoxifen associated uterine pathology in rodents: relevance to women. 876 12

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.
Carcinogenesis 1996 Aug
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

This is the first report on estrogen-dependent growth of human-derived colon carcinoma cells. Under selected conditions, growth of subconfluent Caco-2 cells is triggered by estradiol. Cell growth is estradiol concentration dependent, with maximal effect occurring at about 0.4 nM. Growth is prevented by two different antiestrogens: the partial agonist, OH-Tamoxifen, and the pore antagonist, ICI 182,780. The growth effect is specific for estradiol since other hormonal steroids tested do not affect cell growth. The amount of estradiol receptor in subconfluent Caco-2 cells, detected by blot with monoclonal antibodies directed against the receptor as well as estradiol binding assays, is similar to that of the classical estradiol-responsive, human mammary cancer-derived MCF-7 cells. Estradiol treatment of subconfluent Caco-2 cells rapidly and reversibly stimulates four important intermediates in a signal transduction pathway that is known to trigger cell proliferation: two members of the large family of c-src-related tyrosine kinases, c-src and c-yes, and two serine/threonine kinases, the mitogen-activated protein (MAP) kinases, erk-1 and erk-2. Tyrosine kinases activated by estradiol are up-stream MAP kinases and Caco-2 cell proliferation. In fact, genistein, a specific tyrosine kinase inhibitor, abolishes the estradiol stimulatory effect on both erk-2 activity and cell proliferation. Our findings show that in subconfluent Caco-2 cells, the estradiol-receptor complex activates the c-src, c-yes/MAP kinase pathway and activates growth. This could have important implications for the understanding of human intestinal carcinogenesis.
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PMID:Estradiol activation of human colon carcinoma-derived Caco-2 cell growth. 881 50

Daily intraperitoneal treatment of female Sprague-Dawley rats with either 5, 10 or 20 mg/kg tamoxifen (TAM) for 1 week increased the level of peroxidase activity in the uterus 2- to 10-fold compared to the control level. Using uterine extracts prepared from control and TAM treated animals, we investigated the activation of 4-hydroxytamoxifen (4-HO-TAM) and (E,Z)-1,2-diphenyl-1-(4-hydroxyphenyl)-but-1-ene (cis/trans-metabolite E) to form DNA adducts. Activation of 4-HO-TAM by uterine extracts prepared from either control or TAM-treated rats produced one major (a) and two minor DNA (b and c) adducts. A similar activation of cis/trans-metabolite E produced two adducts (d and e). There was good correlation between levels of uterine peroxidase activity and levels of DNA adducts formed by 4-HO-TAM and cis/trans-metabolite E. Activation of 4-HO-TAM and cis/trans-metabolite E with horseradish peroxidase (HRP) produced the same adducts as observed by activation with uterine extract. Treatment of Sprague-Dawley rats with 5 and 10 mg/kg for 7 days produced eleven DNA adducts in the liver with no adducts detected in the uterus. However, treatment of rats with 20 mg/kg of TAM for 7 days produced the same adduct pattern in the liver and also one major adduct (1) in the uterus with a relative adduct level of 6.4 - 4.1 x 10(-9). Tamoxifen-DNA adduct 1 detected both in the liver and in the uterus of treated rats was similar to adducts produced by activation of 4-HO-TAM with either uterine extract or HRP. The results of these studies suggest a general model whereby the tamoxifen metabolite 4-HO-TAM is further activated in the uterus by peroxidase enzymes to form DNA adducts.
Carcinogenesis 1996 Sep
PMID:Activation of 4-hydroxytamoxifen and the tamoxifen derivative metabolite E by uterine peroxidase to form DNA adducts: comparison with DNA adducts formed in the uterus of Sprague-Dawley rats treated with tamoxifen. 882 96

17beta-estradiol (E2), estrone and diethylstilbestrol (DES) had no effect on nuclear and nucleolar RNA synthesis in vitro. However, after reacting with dimethyldioxirane (DMDO), a versatile epoxide-forming oxidant, these estrogens were able to inhibit and in a dose-dependent manner nuclear and nucleolar RNA synthesis in vitro. It was also found that the time required for the maximal activation of these chemicals by DMDO varied: estrone, 10 min; E2, 30 min; DES, 60 min. Tamoxifen (TAM) was also able to inhibit nuclear and nucleolar RNA synthesis in a dose-dependent manner, but the mechanism of this inhibition was more complex. Control experiments clearly indicated, unlike E2, estrone and DES, TAM per se was able to directly inhibit RNA synthesis in vitro. TAM after activation by DMDO was able to further inhibit RNA synthesis contributing part of the total observed inhibition. These data show for the first time that E2, estrone, DES and TAM can be activated by DMDO and possibly to epoxides. We propose that epoxidation of E2 and estrone may be the underlying mechanism of carcinogenesis for these estrogens in vivo.
Carcinogenesis 1996 Sep
PMID:Activation of 17beta-estradiol and estrone by dimethyldioxirane and inhibition of rat liver nuclear and nucleolar RNA synthesis in vitro. 882 20

Tamoxifen was carcinogenic to the liver of male and female rats, inducing hepatocellular carcinomas when administered daily by gavage or fed continuously in the diet. It also acted as a promoting agent in a two-stage model of carcinogenesis in rat liver. In contrast, tamoxifen acted as a protective agent in abrogating estrogen-induced hepatotoxicity and hepatocarcinogenesis in hamsters. Tamoxifen did not induce malignancies in mice when administered according to dosing protocols that are effective in inducing hepatocellular carcinomas in rat liver. In the rat, tamoxifen is metabolized to alpha-hydroxytamoxifen, which is further activated to a product that binds principally to the exocyclic amino group of deoxyguanosine in DNA. The same adduct pattern is formed in mouse hepatocytes treated with tamoxifen or its alpha-hydroxylated derivative, and in human hepatocytes exposed to the latter metabolite. However, available data indicate that human cells have a substantially lower capacity than rodent cells for activation of tamoxifen. Tamoxifen also induces aneuploidy in rat hepatocytes in vivo. This evidence has led some investigators to characterize tamoxifen as a carcinogen that acts through both genotoxic and nongenotoxic mechanisms, with the implication that women treated with the drug may be consequently subjected to elevated risk of cancer, particularly of the endometrium. Critical examination of the evidence, however, indicates that extrapolation of these experimental data to humans is subject to very substantial uncertainty. Available data clearly indicate major differences between women and rats with respect to the activation of tamoxifen and formation of DNA adducts, and bring into question the validity of direct extrapolation of data generated in the single susceptible species, the rat, to women in assessing potential risks attendant to tamoxifen administration.
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PMID:Review of the toxicology of tamoxifen. 904 21

Tamoxifen-induced DNA adducts were searched in leucocyte DNA from breast cancer patients. Total white blood cell DNA from tamoxifen-treated and control patients was analysed by 32P-postlabelling using HPLC-radioactivity detection. Rat liver DNA was used as a positive standard. In blinded analysis four of the six treated patients showed DNA adducts; none of the five controls were positive. The identity of fraction as a tamoxifen adduct was confirmed by using different chromatographic systems, each with spiked rat liver samples. The level of adducts in the treated patients was 5.5 adducts/10(9) nucleotides as compared to an apparent level of 1.9/10(9) in the controls.
Carcinogenesis 1997 Jan
PMID:Tamoxifen-induced DNA adducts in leucocytes of breast cancer patients. 905 83

Tamoxifen and its analogues 4-hydroxytamoxifen, toremifene, 4-hydroxytoremifene, clomifene and droloxifene were tested for clastogenic effects in a human lymphoblastoid cell line (MCL-5) expressing elevated native CYP1A1 and containing transfected CYP1A2, CYP2A6, CYP2E1 and CYP3A4 and epoxide hydrolase and in a cell line containing only the viral vector (Ho1). MCL-5 or Ho1 cells were incubated with 4-hydroxytamoxifen, 4-hydroxytoremifene, clomifene or droloxifene and the incidence of micronuclei estimated. With MCL-5 cells there was an increase in micronuclei with 4-hydroxytamoxifen, 4-hydroxytoremifene and clomifene but not with droloxifene. With Ho1 cells only 4-hydroxytamoxifen and 4-hydroxytoremifene caused an increase in micronuclei. MCL-5 cells were incubated with tamoxifen, 4-hydroxytamoxifen, toremifene, droloxifene, clomifene or diethylstilbestrol (0.25-10 microg/ml) for 48 h and subjected to 3 h treatment with vinblastine (0.25 microg/ml) to arrest cells in metaphase. The incidence of cells with chromosomal numerical aberrations (aneuploidy) was increased in cells treated with tamoxifen, 4-hydroxytamoxifen, toremifene, clomifene and diethylstilbestrol but not droloxifene. The frequency of cells with structural abnormalities (excluding gaps) was increased in cells treated with tamoxifen and toremifene but not 4-hydroxytamoxifen, clomifene, droloxifene or diethylstilbestrol. The clastogenic activities of tamoxifen (35 mg/kg), toremifene (36.3 mg/kg), droloxifene (35.2 mg/kg) and diethylstilbestrol (25 mg/kg) were compared in groups of four female Wistar rats. Each chemical was dissolved in glycerol formal, administered as a single dose by gavage and hepatocytes isolated by collagenase perfusion 24 h later. The cells were cultured in the presence of epidermal growth factor (40 ng/ml) for 48 h, colchicine (10 microg/ml) being added for the final 3 h of incubation. At least 100 chromosomal spreads were examined from each animal for the presence of numerical and structural abnormalities. The incidences of aneuploidy following treatment were: tamoxifen 81%, toremifene 46%, droloxifene 9.6%, diethylstilbestrol 45.7%, vehicle control 5.3%. The incidences of chromosomal structural abnormalities excluding gaps were: tamoxifen 4.3%, toremifene 0.8%, droloxifene 0.5%, diethylstilbestrol 0.8%, control 0.5%. The incidence of chromosomal structural aberrations excluding gaps in the treated animals was not statistically significantly different from controls except in the tamoxifen-treated group. Tamoxifen (35 mg/kg per os) and toremifene (36.3 mg/kg per os) were dosed to rats for 4 weeks and chromosomal spreads made from hepatocytes. The incidences of aneuploidy were: tamoxifen 94%, toremifene 57%, control 6.5%. The incidences of chromosomal aberrations excluding gaps were: tamoxifen 12%, toremifene 1%, control 0.5%. The incidence of tamoxifen-induced chromosomal structural abnormalities was significantly elevated compared with control levels. The results demonstrate that tamoxifen and toremifene are the only two drugs tested in the study that cause chromosomal structural and numerical aberrations in vitro and tamoxifen is the only drug that induces both these effects in rat liver cells stimulated to divide in culture following oral dosing. Since chromosomal mutations require cell division for their manifestation and tamoxifen is the only compound of those tested that causes hyperplasia in the rat liver, chromosomal aberrations and aneuploidy in the rat liver would only be expected to occur following treatment with tamoxifen alone, although aneuploidy could be induced by toremifene in conjunction with a promoter such as phenobarbitone.
Carcinogenesis 1997 Feb
PMID:Clastogenic and aneugenic effects of tamoxifen and some of its analogues in hepatocytes from dosed rats and in human lymphoblastoid cells transfected with human P450 cDNAs (MCL-5 cells). 905 22

Tamoxifen is a clinically useful estrogen antagonist at or below 10(-6) M concentration. However, above this concentration tamoxifen exerts non-ER mediated cytotoxicity. Such cytotoxic effects are lethal or sublethal. The lethal effects lead to cell death while the sublethal effects may lead to cellular transformation and response modification participating in the process of tumor resistance or even tumor stimulation. Deregulation of intracellular ionized calcium ([Ca2+]i) could lead to genomic instability and deregulation of oncogene expression which might participate in the process of carcinogenesis and/or tumor promotion. Tamoxifen may cause tumor stimulation due to deregulation of [Ca2+]i or its consequences such as activity of protein kinase C, calmodulin and related protein kinases. Precise understanding of such mechanism is important for avoiding tamoxifen induced tumor resistance or tumor stimulation. The deregulation of [Ca2+]i was studied on fluo-3/AM loaded MCF-7 human breast cancer cells following acute and chronic treatment of tamoxifen and calcium ionophore ionomycin. The elevation of [Ca2+]i preceded the death of MCF-7 cells following treatment with ionomycin as previously reported on other cells. Tamoxifen above 10(-6) M also caused an increase in [Ca2+]i preceding the death of MCF-7 cells. However, below this concentration, tamoxifen caused a decrease in [Ca2+]i without any signs of cytotoxicity. The present data clearly demonstrate a tamoxifen-induced increase in [Ca2+]i and cell death only at the concentration-range in which non-E R mediated cytotoxicity is reported.
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PMID:Tamoxifen induces deregulation of [Ca2+] in human breast cancer cells. 913 66


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