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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Each year 3500 new cases of colorectal cancer (13% of total cancer cases) are registered in Switzerland. A yet unknown proportion of these cancers is associated with recently discovered gene defects in one of at Peast 4 genes participating together in an essential process. The function of these genes aims at the correction of certain erroneous hereditary informations that may occur when bases are not or mis-aligned. Mutations leading to anomalies in the expression of one of these genes favour strongly the development of certain early carcinomas, because they lead to an accelerated accumulation of further mutations expected to trigger carcinogenesis. It is estimated that about 2-3/1000 of the population carries a gene error typically manifested as the so called Lynch Syndrome, that concerns not only the colon but also the uterus, ovaries, the urogenital tract and diverse parts of the gastro-intestinal tract. The first observation which led the identification of these genes was a genetic instability within tumor cells showing a distinctly increased mutation rate in many different locations of the genome. Molecular identification of a factor predisposing to malignancy in one of these repair genes permits on one hand to abolish unnecessary investigations in members of families at risk that could be identified as non-carriers of this incriminating mutation and on the other hand to concentrate medical attention on carriers.
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PMID:[Hereditary nonpolyposis colorectal cancer: genetics and prospective molecular screening]. 884 76

To assess the effects of chronic administration of tamoxifen (TAM) and toremifene (TOR) on genetic damage related to carcinogenesis, we measured DNA adduct formation by (32)P-postlabeling in liver, kidney, and uterus of Fischer rats given TAM or TOR in the diet for 18 months. TAM induced high levels of DNA adducts in the liver in a dose-dependent manner. The total adduct levels were 3000 +/- 870 and 6100 +/- 1500 adducts per 10(9) nucleotides for the 250- and 500-ppm groups, respectively. TOR induced a dose-dependent level of adducts that was lower than that observed for TAM. The total hepatic adduct level was 70 +/- 5, 130 +/- 20, and 70 +/- 20 for 250, 500, and 750 ppm TOR, respectively. Both TAM and TOR induced a low level of adducts in the kidney, and TOR significantly enhanced endogenous DNA adduct formation. The total adduct level was 480 +/- 140, 420 +/- 210, and 680 +/- 80 adducts per 10(9) nucleotides for control, 500 ppm TAM, and 500 ppm TOR, respectively. Although neither TAM nor TOR induced adducts in the uterus, TAM significantly enhanced endogenous DNA modifications in this tissue. The total uterine adduct level was 70 +/- 30, 130 +/- 50, and 70 +/- 20 for control, 500 ppm TAM, and 500 ppm TOR, respectively. These observations demonstrate a correlation between DNA adduct formation and carcinogenicity for these compounds. The effectiveness of TOR and TAM in increasing endogenous DNA adducts indicates that a mechanism other than direct DNA damage may also be involved in their carcinogenicity.
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PMID:Effects of chronic administration of tamoxifen and toremifene on DNA adducts in rat liver, kidney, and uterus. 910 42

The high frequency of loss of heterozygosity that has been observed on the distal region of the long arm of chromosome 9 in squamous cell carcinomas of esophagus, lung, uterus, and head and neck indicates the presence of a tumor suppressor gene(s) in this region. To investigate the possible role of the PTC gene on chromosome 9q22.3, that was identified as the cause of nevoid basal cell carcinoma syndrome, during carcinogenesis in esophagus and lung, we examined 20 esophageal squamous cell carcinomas and 10 squamous cell carcinomas of the lung for mutations in any coding exon of PTC. Using single-strand conformation polymorphism and direct sequencing, we detected no mutations other than two non-deleterious polymorphisms. Our results suggest that inactivation of some tumor suppressor gene(s) on 9q other than PTC contributes to the development of squamous cell carcinomas in these tissues.
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PMID:No evidence of mutation in the human PTC gene, responsible for nevoid basal cell carcinoma syndrome, in human primary squamous cell carcinomas of the esophagus and lung. 914 Jan 4

Progesterone is a key developmental, proliferative, and differentiative hormone in the breast and endometrium, and it can accelerate carcinogenesis in the mammary gland epithelium. In the breast and uterus, progesterone acts through two coexpressed isoforms of progesterone receptors, the B- and A-receptors. To study the function of each isoform in isolation, we previously constructed two breast cancer cell lines that stably and independently express either B-receptors (YB cells) or A-receptors (YA cells). In the present study, YA or YB cells were left untreated, or were treated with the synthetic progestin R5020, and the messages present in each cell line under the two conditions were analyzed by differential display. Two message species are described that are regulated only by B-receptors. One of these is regulated in a ligand-independent manner. A third set of messages, encoding flavin-containing monooxygenase 5 (FMO5), was induced by R5020 only in YB cells. A-receptors appear to be inhibitory. FMOs are involved in the metabolic activation of drugs and xenobiotic compounds, including the antiestrogen tamoxifen, to carcinogenic intermediates. It is possible, therefore, that by upregulating the levels of FMO5, progesterone enhances the carcinogenicity of tamoxifen in target tissues that overexpress progesterone B-receptors.
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PMID:Progesterone regulated expression of flavin-containing monooxygenase 5 by the B-isoform of progesterone receptors: implications for tamoxifen carcinogenicity. 928 26

Estrogen is a known risk factor for human breast cancer, although the mechanism by which estrogens induce cancer remains unestablished. We have demonstrated that DNA strand breakage is induced synergistically when pBR322 plasmid DNA is incubated in the presence of both a nitric oxide (NO)-releasing compound (diethylamine NONOate, etc.) and a catechol-estrogen (2- or 4-hydroxyestradiol or -hydroxyestrone). Either the NO-releasing compound or the catechol-estrogen alone induced much fewer strand breaks. Estradiol, estrone, O-methylated catechol-estrogens, and diethylstilbestrol did not exert such DNA damaging effects. Strand breakage induced by NO plus 2- or 4-hydroxyestradiol was inhibited by carboxy-PTIO (an NO-trapping agent) and, to a lesser extent, by superoxide dismutase. Antioxidants (e.g., N-acetylcysteine, ascorbate), but not HO. scavengers, exhibited inhibitory effects. A possible mechanism for this strand breakage would be: (1) NO mediates conversion of catechol-estrogens to quinones, (2) the quinone/hydroquinone redox system produces O2.-, and (3) O2.- reacts with NO to form peroxynitrite, which causes DNA strand breaks. Our results imply that interaction of catechol-estrogens and NO, both known to be formed in human breast and uterus, leads to production of a potent oxidant(s), which could cause damage in cells and DNA, thus playing an important role in hormonal carcinogenesis.
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PMID:Synergistic induction of DNA strand breakage by catechol-estrogen and nitric oxide: implications for hormonal carcinogenesis. 943 10

The induction of preneoplastic and neoplastic lesions by the widely used antiestrogen Tamoxifen was studied in female mice. Outbred CD-1 mice were treated with Tamoxifen (1, 2, 5, 10, 25 or 50 microg/pup/day) for the first 5 days after birth. At 14-17 months, reproductive tract tissues were examined for pathological changes. In the ovary, corpora lutea were lacking while cysts were quite common in Tamoxifen-exposed mice at all doses; cystadenomas were seen in two mice. Structural malformations and epithelial hyperplasia of the oviduct were seen in 100% of the treated mice. Malformations of the uterus, cervix, and vagina were also seen. Excessive vaginal keratinization was not a common feature although vaginal adenosis was observed more often after Tamoxifen treatment than previously reported after similar treatment with diethylstilbestrol (DES). The most striking histological features, however, were seen in the uterus. One hundred percent of the Tamoxifen-treated mice at all doses exhibited uterine hypoplasia with focal areas of basal cell hyperplasia in the lining endometrium. Progressive cellular atypias were seen in the lining endometrium ranging from atypical hyperplasia to uterine adenocarcinoma; the highest incidence of uterine adenocarcinoma was 7/14 (50%) observed in the Tamoxifen 10 microg/pup/day dose group. No similar tumors were observed in corresponding control mice. The induction of atypical uterine hyperplasia and adenocarcinoma combined with other abnormalities observed in genital tract structure following neonatal treatment with Tamoxifen suggests the developing reproductive tract is exquisitely sensitive to perturbation by compounds with hormonal activity. These studies provide the basis for future investigation into the mechanisms of Tamoxifen's carcinogenic effects in experimental animals, and to the risk benefit analysis for the prophylactic use of Tamoxifen in healthy women who are at risk of developing breast cancer.
Carcinogenesis 1997 Dec
PMID:Uterine carcinoma in mice treated neonatally with tamoxifen. 945 Apr 72

Cytochrome P450 enzymes that metabolize estrogens are expressed in the mammary gland, uterus, brain and other target tissues for estrogen action, and this results in the formation of hydroxylated estrogens in these tissues. Estradiol metabolites formed in target tissues at or near estrogen receptors may either be inactive or have important biological effects, and changes in the activities of estrogen-metabolizing enzymes in target tissues may profoundly influence estrogen action. Although some active estrogen metabolites exert hormonal effects in target tissues by interaction with the classical estrogen receptor, other metabolites appear to elicit unique biological responses that are not associated with activation of this receptor. Therefore, some of the many actions of estradiol may not be caused by estradiol per se, but may result from the formation of active estrogen metabolite(s) which function as local mediators or may activate their own unique receptors or effectors. This is an important area in need of more research. The present paper represents a review of the literature and perspectives by the authors on the functional role of estrogen metabolism in target tissues.
Carcinogenesis 1998 Jan
PMID:Functional role of estrogen metabolism in target cells: review and perspectives. 947 88

Catechol estrogens (2- or 4-hydroxyestradiol and 2- or 4-hydroxyestrone) are chemically reactive estrogen metabolites that are O-methylated to less polar monomethyl ethers by catechol-O-methyltransferase, an enzyme present in many tissues such as the liver, kidney, brain, placenta, uterus, and mammary gland. In the present report, we review recent studies on the antitumorigenic and antiangiogenic effects of exogenously administered 2-methoxyestradiol in vitro and in vivo. We also discuss data that suggest that endogenous formation of 2-methoxyestradiol (and its 2-hydroxyestradiol precursor) may have a protective effect on estrogen-induced cancers in target organs. Although the molecular mechanism of action of 2-methoxyestradiol is not clear, we suggest that some unique effects of 2-methoxyestradiol may be mediated by a specific intracellular effector or receptor that is refractory to the parent hormone, estradiol. Additional research is needed to identify factors that regulate the metabolic formation and disposition of 2-methoxyestradiol in liver and in target cells and to evaluate the effects of modulating 2-methoxyestradiol formation on estrogen-induced carcinogenesis.
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PMID:Is 2-methoxyestradiol an endogenous estrogen metabolite that inhibits mammary carcinogenesis? 962 57

The p53 tumor suppressor gene, which is induced by DNA damage and/or stress stimuli, causes cells to undergo G1-arrest or apoptotic death; thus it plays an essential role in human carcinogenesis. We have searched for p53-related genes by using degenerate PCR, and have identified two cDNA fragments similar to but distinct from p53: one previously reported, p73, and the other new. We cloned two major splicing variants of the latter gene and named these p51A and p51B (a human homologue of rat Ket). The p51A gene encodes a 448-amino-acid protein with a molecular weight of 50.9 kDa; and p51B, a 641-amino-acid protein with a molecular weight of 71.9 kDa. In contrast with the ubiquitous expression of p53, expression of p51 mRNA was found in a limited number of tissues, including skeletal muscle, placenta, mammary gland, prostate, trachea, thymus, salivary gland, uterus, heart and lung. In p53-deficient cells, p51A induced growth-suppression and apoptosis, and upregulated p21waf-1 through p53 regulatory elements. Mutations in p51 were found in some human epidermal tumors.
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PMID:Cloning and functional analysis of human p51, which structurally and functionally resembles p53. 966 64


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