Benign Neoplasms of the Colon and Rectum
Philip H. Gordon, Santhat Nivatvongs, Lee E. Smith, Scott Thorn Barrows, Carla Gunn, Gregory Blew, David Ehlert, Craig Kiefer, Kim Martens in Neoplasms of the Colon, Rectum, and Anus, 2007
One of the most difficult problems is the treatment of duodenal adenomas. Bile has been implicated in the pathogenesis of duodenal polyps in patients with FAP. FAP bile has been shown to contain an excess of carcinogens able to form DNA adducts. DNA adducts are chemical modification of DNA, formed by covalent binding of electrophilic carcinogens to DNA, which are implicated in the initiation of carcinogenesis because when they are left unrepaired they can lead to mutations. Modification of the action of these carcinogens may reduce the adduct load to the duodenum and so decrease actual duodenal polyp number. However, in the double-blind randomized placebo-controlled trial conducted by Wallace et al. (170), 26 patients with FAP were randomly assigned to ranitidine, 300 mg daily, or placebo for six months after baseline endoscopy. The result showed that acid suppression therapy does not seem to improve duodenal polyposis.
Polynuclear Platinum Drugs
Astrid Sigel, Helmut Sigel in Metal Ions in Biological Systems, 2004
Polynuclear platinum complexes containing two monofunctional Pt-Cl units are, by definition, bifunctional DNA-binding agents. It is, therefore, of considerable interest to examine their binding with respect to the bifunctional mononuclear compounds. Considerable information has now been accumulated on the structures of such DNA adducts and their biological consequences. The emphasis has paralleled the extensive studies on antitumor activity of this specific class of polynuclear compounds. The general structural motif is represented by [{PtCl(NH3)2}-Y-{PtCl(NH3)2}]m+ and within this motif the effects of linker group (see Figure 1) as well as geometric isomerism have been studied. In this way the contributions of features such as charge and the nature of the chain and chain length to cytotoxicity and DNA conformational changes may be systematically explored.
Epidemiological Approaches to Studying Cancer II
Peter G. Shields in Cancer Risk Assessment, 2005
In contrast to markers of internal dose, which measure the internal level of a compound or its metabolites, markers of biologically effective dose assess the amount of this compound that interacts with critical subcellular or cellular targets. Thus, these markers have the advantage of integrating the effects of both exposure and host susceptibility. For example, certain chemicals can bind covalently to proteins in the cell to form an adduct (Table 2). DNA adduct formation often occurs after metabolic activation of a carcinogen and can be followed by DNA repair. Thus, measurement of adducts can assess both exposure to a specific carcinogen and the individual’s capacity to activate this carcinogen and repair DNA, as well as other possible host factors. Since formation of chemical–DNA adducts are thought to be important in carcinogenesis, individuals with the highest levels of DNA adducts are expected to be at greater cancer risk. A frequent limitation of adduct studies is that samples of target tissues are often not available and that surrogate tissue needs to be used. DNA adducts have limited applications in case-control studies due to the relatively short life of most adducts evaluated to date. However, protein adducts (hemoglobin or albumin adducts) have a longer half-life and, thus, their use may be possible in retrospective studies of early-stage cancers.
Augmentation of diethylnitrosamine–induced early stages of rat hepatocarcinogenesis by 1,2-dimethylhydrazine
Published in Drug and Chemical Toxicology, 2019
Charatda Punvittayagul, Arpamas Chariyakornkul, Teera Chewonarin, Kanokwan Jarukamjorn, Rawiwan Wongpoomchai
It is well established that DNA adducts can lead to gene mutation and subsequently induce carcinogenesis (Rundle 2006, Swenberg et al. 2011). O6-methylguanine is one of the major types of DNA adducts induced by alkylating carcinogens (Kondo et al. 2010). In the present study, the levels of colonic DNA adducts were increased in all carcinogen treated groups. Although DEN induced colonic DNA adducts formation, it did not induce ACF formation, suggesting that these adducts might be involved in neither oncogenes nor tumor suppressor genes. The combined treatment with DEN and DMH significantly increased hepatic DNA adduct formation, whereas colonic DNA adducts did not differ from DEN or DMH alone groups. This may be one reason why DMH promoted DEN-induced hepatic GST-P positive foci formation.
Similarities in mRNA expression of peripheral blood drug metabolizing enzymes and cancer marker genes with biopsy samples of head and neck cancer patients
Published in Biomarkers, 2019
Feza Hasan, Tridiv Katiyar, Shailendra S. Maurya, Vinay Yadav, Sanjay Yadav, Rahul Pandey, Divya Mehrotra, Rahat Hadi, Sudhir Singh, Madan L. Bhatt, Devendra Parmar
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer, representing about 6% of all cases worldwide (Argiris et al.2008). It is well established that tobacco and alcohol are involved in the etiology of HNSCC, though not all tobacco or alcohol users develop HNSCC (Hashibe et al.2009). Majority of the chemical ingredients present in tobacco undergo metabolic activation by cytochrome P450s (CYPs), the major phase I drug metabolizing enzymes (DMEs) to reactive intermediates to exert carcinogenicity. These intermediates if not detoxified by glutathione-S-transferases (GSTs) and other phase II DMEs, bind to tissue macromolecules to produce carcinogenicity (Enoch and Cronin 2010). Formation of DNA adducts, in particular, leads to mutations in oncogenes and represent initiating event of carcinogenesis (Wiencke 2002). In addition to genotoxic effects, non-genotoxic effects also act synergistically in increasing risk to cancer in tobacco induced malignancies by modulating cellular processes through receptor activation and signalling pathways (Chen et al.2011). Genetic polymorphism in CYPs and GSTs has also been reported to increase the risk to tobacco-induced HNSCC and lung cancer (Sato et al.2000, Ruwali et al.2009, Singh et al.2009). Studies from our laboratory have suggested that gene–environment interactions play a significant role in modifying the susceptibility to HNSCC (Maurya et al.2014).
Protective Effects of Pelargonidin against DMBA-Induced Mammary Tumorigenesis in BALB/c Mice through Reduced Oxidative Stress and Lipid Anomalies
Published in Nutrition and Cancer, 2023
Yahyea Baktiar Laskar, Kasturi Bhattacharjee, Moumita Nath, Yashmin Choudhury, Pranab Behari Mazumder, Anupam Das Talukdar
In the present study, the therapeutic potential of pelargonidin was investigated in a chemical-induced murine breast cancer model, and the results were compared with a commonly prescribed SERM drug, tamoxifen. The study also emphasized reaching a plausible mechanism of anti-tumoral activity of pelargonidin against DMBA-induced mammary carcinogenesis. The polycyclic aromatic hydrocarbons (PAH), 7, 12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer is recognized as the earliest ER-positive mouse model, introduced by Medina et al. (51). In addition, Alvardo et al. (52) demonstrated that DMBA-induced mammary carcinomas were positive for both ER and progesterone receptor (PR), with a higher expression of ERα when compared to PR. In the present study, DMBA effectively induced tumorigeneses in the mammary fat-pad of BALB/c mice. Besides, damage to liver tissues was also observed in DMBA-exposed mice, probably due to oral administration of DMBA that was transported via the gastrointestinal tract. The DMBA-induced carcinogenesis initiates mainly by generating free radicals (epoxide) that can bind to DNA, forming DNA adducts. These DNA adducts are capable of promoting mutations that lead to tumor development. In particular, DMBA-induced rodent mammary carcinogenesis is also attributed to the estradiol-mimicking potential of DMBA that help it to bind estradiol receptor (ER) and helps enhance the ER-mediated growth signaling (53).
Related Knowledge Centers
- DNA
- DNA Repair
- DNA Replication
- Molecular Genetics
- Oxidative Stress
- Carcinogen
- Carcinogenesis
- Biomarker
- 7,12-Dimethylbenz(A)Anthracene
- Steric Factor