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

Experimental ovarian carcinogenesis has been investigated in inbred and hybrid strains of mice and induced by a diversity of mechanisms including X-irradiation, oocytotoxic xenobiotic chemicals, ovarian grafting to ectopic or orthotopic sites, neonatal thymectomy, mutant genes reducing germ cell populations, and aging. The mechanisms are briefly reviewed whereby disruptions in the function of graafian follicles results in a spectrum of ovarian proliferative lesions including tumors. The findings in mutant mice support the concept of a secondary (hormonally-mediated) mechanism of ovarian carcinogenesis in mice associated with sterility. Multiple pathogenetic factors that either destroy or diminish the numbers of graafian follicles in the ovary result in decreased sex hormone secretion (especially estradiol-17 beta) leading to a compensatory over-production of pituitary gonadotrophins (particularly luteinizing hormone), which places the mouse ovary at an increased risk to develop tumors. The intense proliferation of ovarian surface epithelium and stromal (interstitial) cells with the development of unique tubular adenomas in response to sterility does not appear to have a counterpart in the ovaries of women.
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PMID:Mechanisms of hormone-mediated carcinogenesis of the ovary in mice. 853 21

Nuclear receptors are important signalling molecules that directly mediate the effects of hormones, vitamins and xenobiotic compounds at the level of gene expression. Several members of this superfamily of proteins have been implicated in receptor-dependent carcinogenesis. In this review, we summarise how these receptors can function as transcription factors with particular emphasis on the mechanism of transcription activation by the human glucocorticoid receptor tau 1 transactivation domain.
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PMID:Mechanisms of transcription activation by nuclear receptors: studies on the human glucocorticoid receptor tau 1 transactivation domain. 853 22

Transcription factor IIIA (TFIIIA), a cysteine-rich regulatory protein, is the prototype for the largest known superfamily of eukaryotic transcription factors. Members of the TFIIIA superfamily contain Cys2His2 zinc finger domains responsible for nucleic acid binding. Xenobiotic metal ions, which lack known biological function, were previously used as probes for the structure and function of steroid hormone receptors which contain Cys2Cys2 zinc finger domains. Structural alterations in cysteine-rich regulatory proteins by such ions in vivo might potentiate carcinogenesis and other disease processes. In the present study cadmium and other xenobiotic metal ions were used to probe the structure and function of TFIIIA. The specific interaction of TFIIIA with the internal control region (ICR) of the 5S RNA gene, as assayed by DNase I protection, was inhibited by Cd2+ ion concentrations of > or = 0.1 microM. Aluminum ions were also found to inhibit the TFIIIA-5S RNA gene interaction, albeit at higher concentrations (> or = 5 microM). Inhibition by either metal ion was not readily reversible. Other xenobiotic metal ions, such as mercury or cesium, were not found to be inhibitory under these conditions. None of these ions at the concentrations used in this study affected the ability of DNase I to digest DNA or restriction enzymes to specifically cleave DNA. Preincubation of TFIIIA bound to 5S RNA with either Cd2+ or Al3+ resulted in subsequent DNA binding upon dilution and RNA removal, whereas preincubation of free TFIIIA with the metal ions resulted in inhibition of subsequent DNA binding. Because 5S rRNA also binds the TFIIIA zinc finger domains, these results indicate that the 5S RNA bound to TFIIIA protects the protein from metal inhibition and implicates the zinc fingers in the inhibition mechanism. The nature of the footprint inhibition indicates that the N-terminal fingers of TFIIIA are affected by the metal ions. Cd2+ and Al3+ ions also inhibited the ability of TFIIIA to bind complementary single-stranded DNA and promote renaturation, as measured by Tris-phosphate agarose gel electrophoresis. This gel assay is sensitive to DNA conformation and Al3+ ions were found to alter the conformation of single- and double-stranded DNA in this assay. The inhibition of TFIIIA function in vitro by xenobiotic metals offers new insights into the structure and function of TFIIIA and TFIIIA-type zinc finger proteins. Inhibition by Cd2+ occurs at much lower concentrations than previously observed with steroid hormone receptors and suggests that Cys2His2 zinc finger proteins may be especially sensitive to such agents in vivo.
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PMID:Inhibition of transcription factor IIIA-DNA interactions by xenobiotic metal ions. 860 Apr 61

Administration of 2-acetylaminofluorene (2-AAF) to rats increased mdr1b expression in Fischer, Wistar and Sprague-Dawley rat livers; however, the response was much smaller in Sprague-Dawley livers. To investigate the basis of this difference we further examined the regulation of the mdr1b gene in hepatocytes isolated from Fischer, Sprague-Dawley and Wistar rats. A time-dependent increase in basal expression of mdr1b but not mdr2 was observed in hepatocytes isolated from all three strains of rats. After 4 days in culture, a larger increase in mdr1b mRNA levels was observed in Fischer and Wistar rat hepatocytes (3.5- and 4.6-fold respectively) than Sprague-Dawley hepatocytes (2-fold). Treatment of primary hepatocytes with 2-AAF caused an induction of mdr1b expression that varied among the three strains. Notably, Sprague-Dawley hepatocytes were not responsive to 2-AAF. In contrast to the parent compound, the electrophilic metabolites N-hydroxy-2-acetylaminofluorene and N-acetoxy-2-acetylaminofluorene caused a dose-dependent induction of mdr1b expression in both Fischer and Sprague-Dawley hepatocytes, indicating that differences in the metabolic activation of 2-AAF between the strains may account for the differences in mdr1b by 2-AAF. Hepatocytes isolated from all three strains of rats showed an equivalent induction of mdr1b after treatment with cycloheximide. Nuclear run-on assays demonstrated that the increases in mdr1b expression with time in culture and after xenobiotic treatment were due to increased transcription.
Carcinogenesis 1996 Mar
PMID:Regulation of mdr1b gene expression in Fischer, Wistar and Sprague-Dawley rats in vivo and in vitro. 863 Nov 30

p53 and Rb gene mutations are intermediate biomarkers useful for the prediction of neoplastic progression in bladder cancers. Previously, we have shown that low CYP3A activity, measured by dapsone N-hydroxylation, and high CYP2D6 activity, assessed by debrisoquine 4-hydroxylation, were significant susceptibility risk factors in developing aggressive bladder cancer. However, no information is available about the relationship between drug/xenobiotic metabolizing enzyme activities and p53/Rb mutations that may suggest mechanisms of bladder carcinogenesis. We evaluated in vivo CYP3A activity by the dapsone recovery ratio (DPRR), CYP2D6 activity by the debrisoquine recovery ratio (DBRR), CYP2C19 activity by the mephenytoin R/S ratio (RSR), N-acetyltransferase activity by the monoacetyl dapsone to dapsone ratio and glutathione-S-transferase M1 (GSTM1) genotype by PCR. In immunohistochemical studies of bladder tumor tissue, over expression of p53 protein was detected with antibody pAb1801 and loss of Rb protein expression was evaluated with antibody PMG3-245 in patients with transitional cell carcinoma of the bladder. Low CYP3A activity was significantly associated with over expression of or mutated p53 protein (P < 0.05). High CYP2D6 activity (within the extensive metabolizer group) was significantly associated with loss of expression of or mutated Rb protein (P < 0.05). Positive p53 staining also predicted aggressive bladder cancer histopathology (P < 0.05, odds ratio 2.9), and the lowest tertile of DPRR predicted p53 positivity (P < 0.01, odds ratio 3.9 comparing means of lower tertile versus upper tertile of DPRR). These selective associations are consistent with the hypothesis that an environmental pro-carcinogen fails to be detoxified by CYP3A which may preferentially induce p53 mutations, whereas, an alternative pro-carcinogen that may be activated by CYP2D6, may selectively induce Rb mutations.
Carcinogenesis 1996 May
PMID:Association of low CYP3A activity with p53 mutation and CYP2D6 activity with Rb mutation in human bladder cancer. 864 Sep 13

The effect of maternal ethanol intake during lactation on neonatal cytochrome P4502E1 was investigated in Sprague-Dawley rats. Dams were exposed to 15% (v/v) ethanol in drinking water from day 1 of lactation to 4, 7 or 14 days postpartum. Significant (P < 0.01) enhancement of both hepatic and renal N-nitrosodimethylamine (NDMA) demethylase, an activity of P4502E1, was observed in lactating mothers given ethanol in drinking water. Demethylase activity also significantly increased (P < 0.01) in the 7- and 14-day livers of both female and male pups and in the 7- and 14-day female and 14-day male kidneys exposed to ethanol through the transmammary route. Cytochrome P4502E1 protein content, assayed by immunoblotting, increased in the maternal liver and kidney of all groups consuming ethanol. Neonatal P4502E1 protein content increased in the 7- and 14-day livers of both sexes and 14-day female kidneys exposed translactationally to ethanol. No effect of ethanol on enzyme activity or protein content of P4502E1 was observed in the liver or kidney of 4-day-old neonates. These results demonstrate the translactational effect of ethanol on neonatal P4502E1 enzyme, which is involved in the metabolism of many low molecular weight xenobiotics, and indicate the possibility of alterations occurring in the kinetics of neonatal drug and xenobiotic metabolism and also in processes connected with perinatal carcinogenesis.
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PMID:Induction of hepatic and renal P4502E1 of neonatal rats exposed translactationally to ethanol. 865 96

The phenomena associated with nongenotoxic carcinogenesis are multifaceted and complex. Nongenotoxic carcinogens stimulate cell replication in the presence or the absence of cytotoxicity. Cell proliferation is pivotal in the neoplastic process, but the extent of its contribution to the development of xenobiotic-induced cancer remains an open question. The search for a better understanding of this process has generated considerable interest and effort, often with the objective of obtaining useful predictors of the tumourigenic potential of xenobiotics. Alterations in the natural balance of endogenous humoural agents that maintain replicative homeostasis results in proliferative stimulation (or inhibition) which may be transient or sustained. The bases for the molecular interaction of these mediators with cellular receptors, trans-cytoplasmic message conveyance, and subsequent nuclear responses leading to xenobiotic-induced mitosis are becoming better understood. Assessment of tissue replicative status has now become established and utilizes biochemical and histological methodology in a routine manner. The increasingly challenging international regulatory environment is demanding greater understanding of the mechanisms that underlie fundamental phenomena and the influences exerted by xenobiotics prior to their registration. While the precise mode of action of an individual xenobiotic may not be known, sound interpretation of toxicological data, including the contribution made by cell replication, creates greater confidence of its safety in the scientific, regulatory, and commercial communities. This article offers a view of cell proliferation from molecular interactions at the cellular level, through practical assessment of cell and tissue replicative status to its utility in contributing to the registration of new drugs and chemicals.
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PMID:Measures of cell replication in risk/safety assessment of xenobiotic-induced, nongenotoxic carcinogenesis. 866 30

Pesticides are high-volume, widely used, environmental chemicals and there is continuous debate concerning their possible role in many chronic human health effects. Because of their known structures, known rates of application, and the presence of a large occupationally exposed population, they are not only important in their own right but are ideal models for the effects of environmental chemicals on the population in general. For reasons that are not always clear, this potential has not been realized. These exposed populations represent an underused asset in the study of the human health effects of environmental contaminants. Chronic effects thought to involve pesticides include carcinogenesis, neurotoxicity, and reproductive and development effects. In this paper we attempt to summarize this concern and, relying to a large extent on studies in our own laboratory, to indicate the importance and present status of studies of the mammalian metabolism of pesticides and indicate the need for further use of this model. Aspects considered include the role of pesticides as substrates for xenobiotic-metabolizing enzymes such as cytochrome P450 and the flavin-containing monooxygenase and their role as inducers or inhibitors of metabolic enzymes. The interaction of pesticides with complex multienzyme pathways, the role of biological characteristics, particularly gender, in pesticide metabolism, and the special role of pesticides at portals of entry and in target tissues are also considered.
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PMID:Pesticides: an important but underused model for the environmental health sciences. 872 14

There has been increasing interest in the interaction of genetic susceptibility and xenobiotic exposures in cancer etiology. Study of gene-environment interactions may increase our ability to characterize relatively low population risks if a substantial proportion of the population cancer burden is attributed to high risk among a smaller group of genetically susceptible members. Further, these studies may provide insight into the mechanism of carcinogenesis, which can help establish the biologic plausibility of an exposure-cancer relationship. Biologic processes important in tumorigenesis that exhibit substantial interindividual differences may function as susceptibility factors. Potential examples include polymorphic enzymes, which activate and detoxify procarcinogens and carcinogens (e.g., certain P450 enzymes, N-acetyltransferase [NAT2], glutathione S-transferase M1), and variation in the capacity to repair DNA. Biologic assays are now available to evaluate many of these functions at the DNA and phenotype level and can be readily incorporated into studies of cancer etiology.
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PMID:Using biomarkers of genetic susceptibility to enhance the study of cancer etiology. 874 1

Many DNA adduct studies have been carried out in occupational groups that have been at a risk of cancer based on epidemiological results relating to exposure decades ago. Even new epidemiological publications on cancer cannot accurately address the effective exposures after about 1970. This is one justification for biomarker studies. Another justification is exposures for which epidemiological studies have not been conducted or have provided inadequate results, in spite of suspicions raised by short-term or animal experiments. The modulation of environment carcinogenesis by host polymorphism in genes for xenobiotic metabolizing and DNA repair enzymes is currently under extensive investigation. The studies relating phenotype/genotype to cancer are presently extended to various end points that may be related to cancer such as DNA adducts and cytogenetic damage. Adjustment for a metabolic phenotype or genotype may also increase the precision in the measurement. Mutations in oncogenes and tumor suppressor genes may give clues to the etiology of cancer.
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PMID:Future research directions in the use of biomarkers. 878 64


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