Browsing by Subject "Carcinogens"

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    Advancing Toxicology-Based Cancer Risk Assessment with Informatics
    (2010-05-03T19:38:33Z) Bercu, Joel P.; Mahoui, Malika; Romero, Pedro R.; Stevens, James L.; Jones, Josette F.; Palakal, Mathew J.
    Since exposure to carcinogens can occur in the environment from various point sources, cancer risk assessment attempts to define and limit potential exposure such that the risk of developing cancer is negligible. While cancer risk assessment is widely used with certain methodologies well accepted in the scientific literature and regulatory guidances, there are still gaps which increase uncertainties when assessing risk including: (1) mixtures of genotoxins, (2) genotoxic metabolites, and (3) nongenotoxic carcinogens. An in silico model was developed to predict the cancer risk of a genotoxin which improved methodology for a single compound and mixtures. Monte Carlo simulations performed with a carcinogenicity potency database to estimate the overall carcinogenic risk of a mixture of genotoxic compounds showed that structural similarity would not likely increase the overall cancer risk. A cancer risk model was developed for genotoxic metabolites using excretion material in both animals and humans to determine the probability not exceeding a 1 in 100,000 excess cancer risk. Two model nongenotoxic compounds (fenofibrate and methapyraline) were tested in short-term microarray studies to develop a framework for cancer risk assessment. It was determined that a threshold for potential key events could be derived using benchmark dose analysis in combination with well developed ontologies (Kegg/GO), which were at or below measured tumorigenic and precursor events. In conclusion, informatics was effective in advancing toxicology-based cancer risk assessment using databases and predictive techniques which fill critical gaps in its methodology.
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    Mushroom Ganoderma lucidum Prevents Colitis-Associated Carcinogenesis in Mice
    (Public Library of Science, 2012) Sliva, Daniel; Loganathan, Jagadish; Jiang, Jiahua; Jedinak, Andrej; Lamb, John G.; Terry, Colin; Baldridge, Lee Ann; Adamec, Jiri; Sandusky, George E.; Dudhgaonkar, Shailesh; Medicine, School of Medicine
    Background: Epidemiological studies suggest that mushroom intake is inversely correlated with gastric, gastrointestinal and breast cancers. We have recently demonstrated anticancer and anti-inflammatory activity of triterpene extract isolated from mushroom Ganoderma lucidum (GLT). The aim of the present study was to evaluate whether GLT prevents colitis-associated carcinogenesis in mice. Methods/principal findings: Colon carcinogenesis was induced by the food-borne carcinogen (2-Amino-1-methyl-6-phenylimidazol[4,5-b]pyridine [PhIP]) and inflammation (dextran sodium sulfate [DSS]) in mice. Mice were treated with 0, 100, 300 and 500 mg GLT/kg of body weight 3 times per week for 4 months. Cell proliferation, expression of cyclin D1 and COX-2 and macrophage infiltration was assessed by immunohistochemistry. The effect of GLT on XRE/AhR, PXR and rPXR was evaluated by the reporter gene assays. Expression of metabolizing enzymes CYP1A2, CYP3A1 and CYP3A4 in colon tissue was determined by immunohistochemistry. GLT treatment significantly suppressed focal hyperplasia, aberrant crypt foci (ACF) formation and tumor formation in mice exposed to PhIP/DSS. The anti-proliferative effects of GLT were further confirmed by the decreased staining with Ki-67 in colon tissues. PhIP/DSS-induced colon inflammation was demonstrated by the significant shortening of the large intestine and macrophage infiltrations, whereas GLT treatment prevented the shortening of colon lengths, and reduced infiltration of macrophages in colon tissue. GLT treatment also significantly down-regulated PhIP/DSS-dependent expression of cyclin D1, COX-2, CYP1A2 and CYP3A4 in colon tissue. Conclusions: Our data suggest that GLT could be considered as an alternative dietary approach for the prevention of colitis-associated cancer.
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    XPC protects against smoking- and carcinogen-induced lung adenocarcinoma
    (Oxford University Press, 2019-04-10) Zhou, Huaxin; Salib, Jacob; Sandusky, George E.; Sears, Catherine R.; Medicine, School of Medicine
    Cigarette smoke (CS) contains hundreds of carcinogens and is a potent inducer of oxidative and bulky DNA damage, which when insufficiently repaired leads to activation of DNA damage response and possibly mutations. The DNA repair protein xeroderma pigmentosum group C (XPC) is primed to play an important role in CS-induced DNA damage because of its function in initiating repair of both bulky oxidative DNA damage. We hypothesized that loss of XPC function will increase susceptibility to developing CS- and carcinogen-induced lung cancer through impaired repair of oxidative DNA damage. Mice deficient in XPC (XPC-/-) exposed to chronic CS developed lung tumors whereas their wild-type littermates (XPC+/+) did not. XPC-/- mice treated with the CS-carcinogen urethane developed lung adenocarcinomas representing progressive stages of tumor development, with lung tumor number increased 17-fold compared with XPC+/+ mice. Mice heterozygous for XPC (XPC+/-) demonstrated a gene-dose effect, developing an intermediate number of lung tumors with urethane treatment. Treatment of XPC-/- mice with the carcinogen 3-methylcholanthrene followed by the proliferative agent butylated hydroxytoluene resulted in a 2-fold increase in lung adenocarcinoma development. Finally, tumor number decreased 7-fold in the lungs of XPC-/- mice by concurrent treatment with the antioxidant, N-acetylcysteine. Altogether, this supports a mechanism by which decreased XPC expression promotes lung adenocarcinoma development in response to CS-carcinogen exposure, due in part to impaired oxidative DNA damage repair.