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Introduction to Cancer
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
DNA methylation and histone acetylation and de-acetylation are thought to play a role in epigenetic control by modulating transcription and chromatin condensation, respectively. These dynamic processes are regulated by enzymes known as methyltransferases and histone acetyltransferases and their counterparts, the histone de-acetylases. The equilibrium between them can be modified by exogenous influences known as epigenetic agents. These can modify methylation or acetylation and thus change the phenotypes of cells epigenetically, without their DNA sequences being altered. Some examples include chemicals such as bromobenzene and butyryl cyclic adenosine monophosphate, the hormone estradiol, and metals such as cadmium, arsenic, and nickel. In addition, radiation and reactive-oxygen species can act as epigenetic modifiers. Zebularine and 5-aza-2′-deoxycytidine, which are capable of inhibiting DNA methylation, are being used for the treatment of cancer (see Chapter 5) and are also being investigated as cancer chemopreventive agents (see Chapter 12).
Molecular Radiation Biology
Published in Kedar N. Prasad, Handbook of RADIOBIOLOGY, 2020
Many biochemical parameters have been measured in human urine after radiation therapy or accidental exposure. Some of these parameters show changes similar to those obtained with animal studies. The deoxycytidine level in human urine markedly increases after radiation therapy treatment.7 This finding has been confirmed by several investigators. In rat urine, the increase in deoxycytidine is linear within a whole-body exposure range of 200–650 R; no such increase has been found in human urine after irradiation.
Paradoxical Sleep (ps) Factors
Published in Shojiro Inoué, Biology of Sleep Substances, 2020
We have recently found that a 10-h nocturnal i.c.v. infusion of deoxycytidine, a pyrimidine nucleoside, dose-related enhanced PS without affecting SWS in rats70 (see Figure 8). The dose of 10 pmol significantly increased the amount of PS, which was due to an elevated occurrence of PS episodes. For detailed experimental data and the chemical structure of deoxycytidine, see Table 2 and Figure 15 of Chapter 4, respectively.
Targeting Aggressive Fibroblasts to Enhance the Treatment of Pancreatic Cancer
Published in Expert Opinion on Therapeutic Targets, 2021
Yuanyuan Yu, Kathleen Schuck, Helmut Friess, Bo Kong
PSC conditioned-medium is found to protect PDAC cells from gemcitabine toxicity. Further investigation reveals that PSCs can secret deoxycytidine, which inhibits gemcitabine conversion in PDAC cells leading to reduced cytotoxic effect [50]. These results suggest that targeting deoxycytidine can be an ideal option to restore gemcitabine sensibility. Also, the pharmacological activation of sst1 somatostatin receptor, which is selectively expressed by CAFs, inhibits the activity of mammalian target of rapamycin/eukaryotic translation initiation factor 4E-binding protein 1 (mTOR/4E-BP1) pathway and the synthesis of secreted proteins including IL-6, promoting the sensitivity of PDAC cells to gemcitabine therapy [51]. In addition, human PDAC-derived CAFs are intrinsically more resistant to gemcitabine compared with chemoresistant pancreatic cancer cell line PANC1 [52]. When exposed to gemcitabine, CAFs promote cancer cell proliferation and gemcitabine resistance through releasing exosomes containing Snail which is a marker for EMT and depletion of Snail has been clarified to ablate gemcitabine resistance by prolonging the overall survival of PDAC mice [52,53].
How to use macrophages to realise the treatment of tumour
Published in Journal of Drug Targeting, 2020
Xiaoyu Zhang, Weinan Li, Jialin Sun, Zhixin Yang, Qingxia Guan, Rui Wang, Xiuyan Li, Yongji Li, Yufei Feng, Yanhong Wang
In recent years, it has been found that certain chemicals produced by TAMs secretion affect the efficacy of drugs. For example, TAMs can secrete IL-6, which can activate STAT3 in small cell lung cancer cells, and then produce resistance to carboplatin, cisplatin and doxorubicin [17]. In addition, cathepsin B secreted by TAMs can also induce paclitaxel resistance. It is reported that paclitaxel is protected by TAMs in tumour therapy, and the main reason for resistance is that cathepsin secreted by TAMs protects tumour cells [18]. In addition, TAMs can release pyrimidine compounds. The deoxycytidine in this pyrimidine metabolite has a structural similarity with gemcitabine, a first-line chemotherapy drug, which can inhibit the ability of gemcitabine to kill cancer cells [19]. In addition, TAMs can make antitumor drugs tolerable by participating in phenotypic transformation, and interacting with other immune cells in the TME [20–23].
In vitro inhibition of human nucleoside transporters and uptake of azacitidine by an isocitrate dehydrogenase-2 inhibitor enasidenib and its metabolite AGI-16903
Published in Xenobiotica, 2019
Zeen Tong, Usha Yerramilli, Sylvia Yao, James D. Young, Matthew Hoffmann, Sekhar Surapaneni
A clinical study may be warranted to evaluate the interactions between enasidenib and azacitidine. However, since the active form of azacitidine is intracellular triphosphates of azacitidine and 5-aza-2′-deoxycytidine (Issa and Kantarjian, 2009; Kuykendall, 2005; Li et al., 1970; Quintas-Cardama et al., 2010), plasma azacitidine level may not correlate with clinical response, and therefore a pharmacokinetic interaction study may not reflect the pharmacological interactions between enasidenib and azacitidine. It has been published that the plasma level of decitabine (5-aza-2′-deoxycytidine) did not correlate with disease response (Wang et al., 2013). A reliable and reproducible analytical method is still not available to study pharmacodynamic interactions with azacytidine. All methods published in literature for quantification of DNA and RNA adducts as well as triphosphates derived from azacitidine have limitations such as lack of quality reference standards or unpractical sample sizes (Anders et al., 2016; Derissen et al., 2014; Oz et al., 2014; Unnikrishnan et al., 2018; Wang et al., 2013).