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Radiation Hormesis in Cancer
Published in T. D. Luckey, Radiation Hormesis, 2020
Comparable results and conclusions were obtained by injection of a carcinogen, methyl-cholanthrene.489 Mice which survived 5 Gy exposure to X-rays were allowed about a month to recover and then exposed to 2.5 Gy. Following another recovery period, 76 irradiated mice and 79 control mice were injected with methylcholanthrene. When compared with controls (Figure 6.28) the irradiated mice had a longer latent period before palpable tumors could be found and consistently had a lower tumor incidence. At 10 weeks, 6% of the controls, and no irradiated mice, had palpable tumors. This decrease in tumor incidence was statistically significant, p <0.01, from day 96 to day 129. At the end of the experiment 20% of the controls and 31% of the exposed mice had no tumors, a difference of 155%. While it is possible that survival of the 5 Gy exposure was a selection factor, the numbers of tumors which arose at sites remote from the injection were comparable in exposed and control animals. The authors conclude: “…there was, as has been seen, an inhibition of tumor formation by irradiation.”489 Note that irradiation coincidental with, or following administration of, the carcinogen may promote tumor growth.306
Experimental Lung Carcinogenesis by Intravenous Administration
Published in Joan Gil, Models of Lung Disease, 2020
Stanton and Blackwell (1961) examined the effects of pulmonary infarction on lung carcinogenicity of 3-methylcholanthrene by IV administration. They found increased lung tumor incidences in rats when 3-methylcholanthrene was mixed with the infarct-inducing vesicles and injected intravenously.
Experimental Oral Carcinogenesis
Published in Samuel Dreizen, Barnet M. Levy, Handbook of Experimental Stomatology, 2020
Samuel Dreizen, Barnet M. Levy
A special interest in the carcinogenic hydrocarbons was aroused when one of the most active polycyclic hydrocarbons, 20-methylcholanthrene, was synthesized from bile acids. Because the structural resemblance among the carcinogenic hydrocarbons to cholesterol, bile acids, and steroid hormones was so obvious, hopes were high that a common molecular structure, one that was elaborated by the body, would clarify the cancer problem. Thus, the polycyclic hydrocarbons have been intensively studied for their carcinogenic activity by many workers. They are known as “universal carcinogens” because they induce malignant disease after topical application, after injection s.c., after injection i.m or i.v., or after feeding. Because most of the work in experimental carcinogenesis has been done on skin, most is known about skin cancer.
Through a glass, darkly? HepaRG and HepG2 cells as models of human phase I drug metabolism
Published in Drug Metabolism Reviews, 2022
Lesley A. Stanley, C. Roland Wolf
The HepG2 cell line, established by Knowles et al. (1980), was soon shown to be capable of activating cyclophosphamide to genotoxic products, resulting in sister chromatid exchanges, and to exhibit some benzphetamine N-demethylation activity (Dearfield et al. 1983). It could hydroxylate 7-ethoxycoumarin, this activity being induced 20- to 30-fold after 3–4 days’ exposure to 3-methylcholanthrene (3-MC, 5 µM) (Dawson et al. 1985). No induction was detected using phenobarbital (PB). Subclones with higher P450-dependent activities were subsequently isolated. One of these, HepG2/C3A, exhibited 7-ethoxyresorufin and phenacetin O-deethylase activities consistent with the expression of cytochrome P450 (CYP) 1A2 and responded to 3-MC with up to 40-fold induction (Kelly and Sussman 2000). This cell line was patented (Patent Numbers US5290684A, 1994 and US6653105B2, 2003) and used to develop a commercial fluorescence-based assay for CYP1A2 induction; these patents have expired and the HepG2/C3A cell line is available from the American Type Culture Collection (ATCC HB-8065).
Role of p53 in the chronic pulmonary immune response to tangled or rod-like multi-walled carbon nanotubes
Published in Nanotoxicology, 2018
Katherine S. Duke, Elizabeth A. Thompson, Mark D. Ihrie, Alexia J. Taylor-Just, Elizabeth A. Ash, Kelly A. Shipkowski, Jonathan R. Hall, Debra A. Tokarz, Mark F. Cesta, Ann F. Hubbs, Dale W. Porter, Linda M. Sargent, James C. Bonner
There is concern that MWCNTs might behave like asbestos, which has been shown to cause pulmonary fibrosis and mesothelioma in humans and animal models. Like asbestos, MWCNTs delivered to the lungs of mice cause pulmonary fibrosis and lung cancer (Porter et al. 2010; Sargent et al. 2014). MWCNTs delivered to the lungs of mice by inhalation also cause interstitial, airway and sub-pleural fibrosis but not granulomas (Ryman-Rasmussen et al. 2009b), whereas oropharyngeal aspiration (OPA) causes both pulmonary fibrosis and granuloma formation (Muller et al. 2005; Dong et al. 2015; Duke et al. 2017). MWCNTs also reach the pleura of mice after inhalation or aspiration and cause inflammatory lesions at the mesothelial lining and proliferation of mesothelial cells (Ryman-Rasmussen et al. 2009a; Xu et al. 2012; Mercer et al. 2013). Increased promotion of adenocarcinomas was reported in mice that were first exposed to the tumor initiator methylcholanthrene (MCA) followed by exposure to rod-like MWCNTs (Sargent et al. 2014). That study also showed serosal tumors morphologically consistent with sarcomatous mesotheliomas in five mice co-exposed to MCA and MWCNTs and in one mouse from the MCA control treatment group, but none resulting from MWCNT exposure alone.
Proteases, protease inhibitors and radiation carcinogenesis
Published in International Journal of Radiation Biology, 2023
Our hypotheses related to the potential mechanisms for the suppression of radiation carcinogenesis by APIs include their ability to affect certain proteases and proteolytic activities (as described above) as well as having effects on gene amplification and expression levels of certain oncogenes (e.g. c-myc, c-fos, c-erb B2/neu and c-H-ras) (Kennedy 1994, 1998c). Our hypothesis is that radiation exposure (at carcinogenic doses) gives rise to an ongoing process which is induced as a heritable epigenetic change (Kennedy et al. 1980; Kennedy and Little 1981; Kennedy et al. 1984; Kennedy and Little 1984; Kennedy 1985b, 1998c). During proliferation of the irradiated/initiated cells, malignantly transformed cells arise later from what appears to be a mutagenic event (Kennedy et al. 1984; Kennedy and Little 1984). It is hypothesized that the APIs are able to stop this ongoing process, which results in a reduction in the number of irradiated/initiated cells that give rise to malignant cells (Kennedy 1994). There is evidence that such a high frequency initiating event also occurs in 3-methylcholanthrene induced malignant transformation in vitro (Fernandez et al. 1980), and in radiation induced carcinogenesis in vivo (Kennedy 1994). One example of such an ongoing process is radiation induced recombination in yeast (Fabre and Roman 1977), which is an ongoing process that can be turned off by chymotrypsin inhibitors (Wintersberger 1984). While our observations on radiation induced carcinogenesis that led to the hypotheses described here were published several decades ago when heritable epigenetic changes were not being widely discussed as possible causes of cancer, the current thoughts on the causes of cancer recognize the importance of heritable epigenetic changes in tumor initiation and progression as well as in cancer prevention (e.g. Baylin and Jones 2016).