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Chemical Carcinogenesis (chemical + carcinogenesi)
Selected AbstractsExpression of the human Cathepsin L inhibitor hurpin in mice: skin alterations and increased carcinogenesisEXPERIMENTAL DERMATOLOGY, Issue 9 2007Markus Walz Abstract:, The serine protease inhibitor (serpin) hurpin (serpin B13) is a cross class-specific inhibitor of the cysteine protease Cathepsin (Cat) L. Cat L is involved in lysosomal protein degradation, hair follicle morphogenesis, epidermal differentiation and epitope generation of antigens. Hurpin is a 44 kDa protein which is expressed predominantly in epidermal cells. In psoriatic skin samples, hurpin was strongly overexpressed when compared with normal skin. Keratinocytes overexpressing hurpin showed increased resistance towards UVB-induced apoptosis. To further analyse the functional importance of this inhibitor, we have generated transgenic mice with deregulated Cat L activity by expressing human hurpin in addition to the endogenous mouse inhibitor. The three independent transgenic lines generated were characterized by identical effects excluding insertional phenotypes. Macroscopically, mice expressing human hurpin are characterized by abnormal abdominal fur. The number of apoptotic cells and caspase-3 positive cells was reduced after UV-irradiation in transgenic animals compared with wild-type mice. Interestingly, after chemical carcinogenesis, transgenic mice showed an increased susceptibility to develop skin cancer. Array analysis of gene expression revealed distinct differences between wild-type and hurpin-transgenic mice. Among others, differentially expressed genes are related to antigen presentation and angiogenesis. These results suggest an important role of Cat L regulation by hurpin which might be of clinical relevance in human skin diseases. [source] High salt diets dose-dependently promote gastric chemical carcinogenesis in Helicobacter pylori -infected Mongolian gerbils associated with a shift in mucin production from glandular to surface mucous cellsINTERNATIONAL JOURNAL OF CANCER, Issue 7 2006Sosuke Kato Abstract Intake of salt and salty food is known as a risk factor for gastric carcinogenesis. To examine the dose-dependence and the mechanisms underlying enhancing effects, Mongolian gerbils were treated with N -methyl- N -nitrosourea (MNU), Helicobacter pylori and food containing various concentrations of salt, and were sacrificed after 50 weeks. Among gerbils treated with MNU and H. pylori, the incidences of glandular stomach cancers were 15% in the normal diet group and 33%, 36% and 63% in the 2.5%, 5% and 10% NaCl diet groups, showing dose-dependent increase (p < 0.01). Intermittent intragastric injection of saturated NaCl solution, in contrast, did not promote gastric carcinogenesis. In gerbils infected with H. pylori, a high salt diet was associated with elevation of anti- H. pylori antibody titers, serum gastrin levels and inflammatory cell infiltration in a dose-dependent fashion. Ten percent NaCl diet upregulated the amount of surface mucous cell mucin (p < 0.05), suitable for H. pylori colonization, despite no increment of MUC5AC mRNA, while H. pylori infection itself had an opposing effect, stimulating transcription of MUC6 and increasing the amount of gland mucous cell mucin (GMCM). High salt diet, in turn, decreased the amount of GMCM, which acts against H. pylori infection. In conclusion, the present study demonstrated dose-dependent enhancing effects of salt in gastric chemical carcinogenesis in H. pylori -infected Mongolian gerbils associated with alteration of the mucous microenvironment. Reduction of salt intake could thus be one of the most important chemopreventive methods for human gastric carcinogenesis. © 2006 Wiley-Liss, Inc. [source] Thymoquinone supplementation induces quinone reductase and glutathione transferase in mice liver: possible role in protection against chemical carcinogenesis and toxicityPHYTOTHERAPY RESEARCH, Issue 9 2009Mahmoud N. Nagi Abstract Thymoquinone (TQ), the main constituents of the volatile oil from Nigella sativa seeds is reported to protect laboratory animals against chemical carcinogenesis and toxicity through mechanism(s) that is not fully understood. Among possible mechanism(s), protection could be mediated via induction of detoxifying enzymes, including quinone reductase and glutathione transferase. This study was undertaken to investigate whether oral administration of TQ increases the activities of quinone reductase and glutathione transferase in mice liver. Overdose of TQ, when administered intraperitoneally, caused a marked depletion of hepatic glutathione in both a time- and dose- dependent manner, a characteristic of a group of compounds known as Michael reaction acceptors which are known to act as inducers of enzymes that protect against chemical carcinogenesis and toxicity. TQ was given (1, 2 and 4 mg/kg/day p.o.) for five days to test the chemical inducibility of quinone reductase and glutathione transferase in mice liver. TQ administration produced significant increase in the activities of quinone reductase (147, 196 and 197% of control, respectively) and glutathione transferase (125, 152 and 154% of control, respectively). In conclusion, oral administration of TQ is effective in increasing the activities of quinone reductase and glutathione transferase and makes TQ a promising prophylactic agent against chemical carcinogenesis and toxicity. Copyright © 2009 John Wiley & Sons, Ltd. [source] DNA repair and cancer: Lessons from mutant mouse modelsCANCER SCIENCE, Issue 2 2004Takatoshi Ishikawa DNA damage, if the repair process, especially nucleotide excision repair (NER), is compromised or the lesion is repaired by some other error-prone mechanism, causes mutation and ultimately contributes to neoplastic transformation. Impairment of components of the DNA damage response pathway (e.g., p53) is also implicated in carcinogenesis. We currently have considerable knowledge of the role of DNA repair genes as tumor suppressors, both clinically and experimentally. The deleterious clinical consequences of inherited defects in DNA repair system are apparent from several human cancer predisposition syndromes (e.g., NER-compromised xeroderma pigmentosum [XP] and p53 -deficient Li-Fraumeni syndrome). However, experimental studies to support the clinical evidence are hampered by the lack of powerful animal models. Here, we review in vivo experimental data suggesting the protective function of DNA repair machinery in chemical carcinogenesis. We specifically focus on the three DNA repair genes, O6 -methylguanine-DNA methyltransferase gene (MGMT), XP group A gene (XPA) and p53. First, mice overexpressing MGMT display substantial resistance to nitrosamine-induced hepatocarcinogenesis. In addition, a reduction of spontaneous liver tumors and longer survival times were evident. However, there are no known mutations in the human MGMT and therefore no associated cancer syndrome. Secondly, XPA mutant mice are indeed prone to spontaneous and carcinogen-induced tumorigenesis in internal organs (which are not exposed to sunlight). The concomitant loss of p53 resulted in accelerated onset of carcinogenesis. Finally, p53 null mice are predisposed to brain tumors upon transplacental exposure to a carcinogen. Accumulated evidence in these three mutant mouse models firmly supports the notion that the DNA repair system is vital for protection against cancer. [source] | ||||||||||