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The Human Cancer Situation
Published in Samuel C. Morris, Cancer Risk Assessment, 2020
Further direct DNA damage may also enter at this stage. There is some evidence that transformation of a benign tumor to a malignant tumor could be caused by a second-hit phenomenon in a benign tumor cell (Anderson, 1987). Mutagenic activation of ras oncogenes have been shown to occur late in the carcinogenic process, initiating the transition of a polyp to a malignant carcinoma or to convert a primary melanoma into a metastic tumor (Bos, 1988). DNA damage and other important forces of change may also be produced by the tumor’s own growth. During the progression stage, the tumor becomes much more complex. In the early, high cell-proliferation stage, proliferating cells are usually located within a few cell layers of blood vessels. Quiescent and necrotic cells are further away from blood vessels (Sutherland, 1988). As the tumor grows, its microenvironment becomes more heterogeneous. Sharp gradients in availability of oxygen, glucose, lactate, H+ ions, and other nutrients, hormones, and growth factors develop. These microenvironmental changes exert selective pressure and new and diverse cell phenotypes emerge. Differentiated quiescent cells also emerge under the influence of this altered cellular environment. At the same time, natural biological response modifiers are present which can induce either cell proliferation or quiescence. These may cause cells to become quiescent and, at a later stage, reactivate them to cause a resurgence of growth in the tumor.
Toxicogenomics in Toxicologic Pathology
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Arun R. Pandiri, David E. Malarkey, Mark J. Hoenerhoff
Genotoxic mechanisms of direct DNA damage are a hallmark of carcinogenesis. Prediction of carcinogenicity of compounds in vitro, using standard genotoxicity assays, is the current standard by which prediction of genotoxic mechanisms is measured. However, current assays that are used to detect genotoxicity are somewhat imprecise, have low specificity, and are generally insufficient to model the complex disease of cancer, and can often over-predict carcinogenesis, leading to false-positive results (Ellinger-Ziegelbauer et al. 2008, 2009; Kirkland et al. 2005; Kirkland et al. 2006; Ward 2007). In addition, over ½ of chemically induced tumors are caused by non-genotoxic compounds, which are difficult to predict in short-term assays (Nie et al. 2006). Furthermore, non-genotoxic compounds may induce a genotoxic response in vitro using current genotoxicity assays, due to secondary mechanisms of DNA damage, as discussed previously. This makes interpretation of genotoxicity data for non-genotoxic compounds confusing and difficult in terms of human risk assessment. In fact, the ability to predict carcinogenicity in humans as a result of these assays has been questioned (Ellinger-Ziegelbauer et al. 2009; Kirkland et al. 2006; Waters et al. 2010). Additionally, since non-genotoxic mechanisms may be dictated or influenced by a dose response and be subject to a no adverse effect level (NOAEL), both the assessment of mechanism as well as prediction of carcinogenesis based on dose response, are important for non-genotoxic compounds relative to risk assessment.
Genotoxic Potential of Ayurvedic Formulations
Published in Saroya Amritpal Singh, Regulatory and Pharmacological Basis of Ayurvedic Formulations, 2017
Genotoxicity describes the property of chemical agents that damages the genetic information within a cell causing mutation, which may lead to cancer. The alteration can have direct or indirect effects on the DNA: the induction of mutations, mistimed event activation and direct DNA damage leading to mutations.
Genomic DNA damage induced by co-exposure to DNA damaging agents and pulsed magnetic field
Published in International Journal of Radiation Biology, 2023
Beatriz López-Díaz, Silvia Mercado-Sáenz, Antonio M. Burgos-Molina, Alejandro González-Vidal, Francisco Sendra-Portero, Miguel J. Ruiz-Gómez
Due to the low energy that low-frequency MF deposit in the tissues they pass through, the occurrence of direct DNA damage (DNA single or double strand break) (genotoxic effect) is unlikely. DNA breaks are very efficiently repaired in cells, so they are hidden and hardly noticeable. The co-exposure to MF and genotoxic agents (additive effect) allows to observe with greater probability the alterations in the DNA damage that could occur (Ruiz-Gómez and Martínez-Morillo, 2009). Even so, there are many articles that describe direct damage to the DNA molecule by exposure to MF alone. In this sense, we reported an increment in the degradation of genomic DNA in S. cerevisiae cells that were exposed to the same type of pulsed MF but with different exposure time (8 h/d) during chronological aging (40 d) (Mercado-Sáenz et al. 2021). Considering isolated genomic DNA molecules as an experimental model, we found previously a 20.7-fold increase in genomic DNA degradation, in relation to controls, after exposure of DNA to pulsed MF during 16 d (López-Díaz et al. 2014).
Cell cycle dysregulation on prenatal and postnatal arsenic exposure in skin of Wistar rat neonates
Published in Xenobiotica, 2023
Navneet Kumar, Astha Mathur, Suresh Kumar Bunker, Placheril J. John
Arsenic induced mitotic disruption is regulated by p53 (Taylor et al. 2006). Our study demonstrated a consistent significant increase in the transcript level expressions of p53, p21 and p27 in LDG, MDG and HDG in comparison to control groups. It is well known that one of the most significant tumour-suppressing genes in maintaining genomic integrity and preventing carcinogenesis is p53. A variety of pleiotropic processes are regulated by p53 in order to repair cellular damage and preserve homeostasis in the context of acute DNA damage, oncogene dysregulation, and other types of cellular stress (Mollereau and Ma 2014). Furthermore, the increased p53 translational activity may cause G2 block. p53 activates p21 transcriptionally, and p21 inhibits CDK2 (G1/S-CDK and S-CDK) and binds to PCNA (proliferating cell nuclear antigen), an accessory component of DNA polymerases δ and ε, to prevent cell proliferation in reaction to the DNA damage or stress on replication (Coqueret 2003; De Renty et al. 2014). Similarly, p27 inhibits the same CDKs that p21 targets and aids cells in exiting the cell cycle during terminal differentiation (Ding et al. 2009). Although arsenic is not responsible for direct DNA damage, it targets the enzymes involved in base excision and nucleotide excision repair processes, which is further responsible for DNA damage and activation of the p53 tumour suppressor gene (Ebert et al. 2011; Shen et al. 2013).
Non-targeted effects of radiation: a personal perspective on the role of exosomes in an evolving paradigm
Published in International Journal of Radiation Biology, 2022
Munira Kadhim, Seda Tuncay Cagatay, Eman Mohammed Elbakrawy
In the early 1990s, analysis of experimental data on the biological effects of radiation started to raise doubts about results that challenged the conventional paradigm that genetic alterations are restricted to direct DNA damage. These observations ushered a paradigm shift toward the NTE of radiation whereby cells that are not exposed to ionizing radiation show responses similar to those observed with direct radiation exposure. The NTE paradigm was first demonstrated in the descendants of irradiated cells which is now referred to as radiation-induced genomic instability (GI). Moreover, similar effects were soon observed in un-irradiated cells that were either in contact or receive signals from irradiated cells, a phenomenon currently known as radiation-induced bystander effect (RIBE). I am pleased that I contributed to the first pioneering manuscript (Kadhim et al. 1992) on this paradigm shift while working at the Medical Research Council (MRC) Radiobiology Unit, UK. We observed enhanced frequencies of non-clonal chromosomal aberrations in clonal descendants of mouse hematopoietic stem cells examined 12–14 generations following alpha radiation exposure. This was then extended in Kadhim et al. (1994) by showing these phenomena occur in human hematopoietic stem cells (Kadhim et al. 1994). We also discovered a genetic factor contributed to the induction of these effects, and thereby provided more evidence supporting the hypothesis that the instability phenotype is determined by genetic predisposition.