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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Despite much research on the medicinal chemistry and pharmacology of the nitrogen mustards, their precise mechanism of action at the molecular level and selectivity for tumor cells remains elusive. However, it has been established that they form mono-alkylated DNA adducts, along with intrastrand and interstrand cross-links in the minor groove. The latter are the most toxic lesions for cells, as the two strands of DNA are effectively “stapled” together via covalent interactions with the N7-positions of guanine bases on opposite DNA strands. It has been demonstrated in vitro that these interstrand adducts block replication and inhibit enzymes such as ribonucleic acid (RNA) polymerase. It can also be demonstrated by electrophoresis-based experiments and molecular modeling that mustard adducts (particularly interstrand cross-links) distort the helical structure of DNA, and this effect can be transmitted through a number of base pairs (i.e., a teleometric effect). Therefore, DNA processing may also be affected at a point distant from the adduct sites. Apart from the kinetic (i.e., killing faster-growing cells) or repair (i.e., cancer cells being repair-deficient compared to normal cells) explanations for the selectivity of the nitrogen mustards, another possibility is that their GC-selectivity may play a role. For example, it is known that some of the gene sequences associated with Burkitt’s lymphoma are particularly GC-rich, and this disease is highly responsive to cyclophosphamide which cross-links guanine bases.
Adverse Effects and Intoxication with Essential Oils
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
However, the carcinogenic potency appears to be relatively low and dependent on the metabolism. Safrole is metabolically activated through the formation of intermediates, and these are able to directly react with DNA. Two bioactivation pathways of safrole to potentially hepatotoxic intermediates have been reported. One involves P450-catalyzed hydroxylation, thereby producing 1′-hydroxysafrole, and on further conjugation with sulfate, generating a reactive sulfate ester. This ester creates a highly reactive carbocation, which alkylates DNA. The second pathway involves P450-catalyzed hydroxylation of the methylenedioxy ring and finally formation of reactive p-quinone methide. Both pathways could explain the genotoxic effects of safrole. DNA adducts have been identified in vitro and in vivo (see Dietz and Bolton, 2005).
Measurement of Exposure and Dose
Published in Samuel C. Morris, Cancer Risk Assessment, 2020
Especially exciting opportunities for biomarkers of exposure are found in DNA adducts. The active forms of many chemical carcinogens are metabolites which bind to cellular macromolecules, including nucleic acids and proteins; the product of these bindings are called adducts. The formation of DNA adducts are thought by many to be cancer-initiating events (Wogan and Tannenbaum, 1987). What better index of the biologically effective dose than the actual dose causing the initiating event itself. As discussed earlier (Chap. 2), in addition to initiation, the progression step in carcinogenesis may also require a DNA-damaging event. Thus, DNA adducts may be indicators of exposure affecting both early and late steps in cancer development (Harris, 1985). Much work has been done to build an understanding of the relationship between exposure or, in experimental animals, administered dose, and the levels of DNA adducts. A linear relationship is often, but not always, found (Perera, 1987; Belinsky et al., 1987; Adriaenssens et al., 1983; Dunn, 1983). Pharmacokinetics, discussed in a later chapter, rules this relationship.
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).
Toxicological profile of lipid-based nanostructures: are they considered as completely safe nanocarriers?
Published in Critical Reviews in Toxicology, 2020
Asaad Azarnezhad, Hadi Samadian, Mehdi Jaymand, Mahsa Sobhani, Amirhossein Ahmadi
Free radicals can react with DNA and cause cross-links that lead to the formation of 8-hydroxydeoxyguanosine DNA adducts (8-OHdG). This metabolite resulting from oxidative stress damage has a mutagenic potential and has been observed to be accumulated in breast tumor cells. Therefore, its measurement can be used as a marker to evaluate the genetic toxicity of different materials (Gharagozloo et al. 2016). Detection of the 8-OHdG DNA adduct can be performed by various methods; however, the most sensitive methods are HPLC and gas chromatography coupled with mass spectrometry (GC-MS) based techniques. Antibody-based techniques such as immunofluorescence, immunohistochemistry or DNA dot blots which involve the detection of an antibody attached to the 8-OHdG adduct might also be used as the alternative approached of 8-OHdG adduct detection (Ng et al. 2010).
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.