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Mechanisms of Different Anticancer Drugs
Published in Anjana Pandey, Saumya Srivastava, Recent Advances in Cancer Diagnostics and Therapy, 2022
Anjana Pandey, Saumya Srivastava
Fluorouracil is broadly metabolized and it possesses two separate and specific action mechanisms. In one mechanism, DNA synthesis is prevented as fluorouracil is metabolized to fluorodeoxyuridine monophosphate, which stops thymidylate synthetase (Zhang et al., 2008). In another mechanism, it can also interfere with the synthesis of RNA and protein. The specific mechanism of fluorouracil lethalness differs probably between tissues according to the effects of fluorouracil on the metabolism of RNA and biosynthesis of thymidine (Longley et al., 2003). Metabolism of fluorouracil is also influenced by the simultaneous administration of allopurinol and thymidine (Calman, 2015). It is depicted that the rate response of this drug is associated with a high dose during treatment.
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Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Eun-Kyung Lim, Taekhoon Kim, Soonmyung Paik, Seungjoo Haam, Yong-Min Huh, Kwangyeol Lee
MTX inhibits the action of the FA reductase, which is responsible for conversion of FA to tetrahydrofolic acid [362, 363]. In the absence of tetrahydrofolic acids, DNA, RNA, and proteins cannot be synthesized, leading to blockage of cell division. Hydroxyurea (hyhdroxycarbamide) reduces production of deoxyribonucleotides through inhibition of the enzyme ribonucleotidereductase [361–366]. This enzyme catalyzes the reduction of ribonucleotide into their corresponding deoxyribonucleotides, which are required for DNA synthesis. 5-FU, a thymidylate synthase inhibitor, is widely used in the treatment of patients with breast or gastrointestinal tract cancer. Interrupting the action of this enzyme blocks the synthesis of pyrimidine thymidine, which is a nucleoside required for DNA replication, in the S phase of the cell cycle [367]. Thymidylate synthase converts deoxyuridine monophosphate (dUMP) into deoxythymidine monophosphate (dTMP), which is crucial in production of pyrimidine base for synthesis of DNA; thus, it is a viable target for cancer chemotherapy [367]. 5-FU causes a scarcity of dTMP. Therefore, rapidly dividing cancer cells undergo apoptosis via thymine-less death. 5-FU can arrest unlimited proliferation of cancer cells and also lead to production of faulty rRNA [368, 369]. The immunosuppressive drug 6-MP alters the synthesis and function of DNA and RNA by inhibiting purine nucleotide synthesis and metabolism and interferes with nucleotide interconversion and glycoprotein synthesis [370, 371].
Biochemistry
Published in Ronald Fayer, Lihua Xiao, Cryptosporidium and Cryptosporidiosis, 2007
Plasmodium and Toxoplasma (and probably many other apicomplexans) are capable of synthesizing pyrimidines de novo from glutamine (Gardner et al., 2002; Kim and Weiss, 2004). However, Cryptosporidium lacks a de novo pathway, and relies on nucleotide transporters for scavenging pyrimidines. This parasite makes UMP via two uracil phosphoribosyltransferases (UPRTs): one is a discrete enzyme, whereas the other is fused with uridine kinase (UK-UPRT). UK is also responsible for synthesizing CMP from cystidine, and thus is also termed as uridine-cystidine kinase. Cryptosporidium also possesses a bacterial-type thymidine kinase (TK) to synthesize dTMP that can be further converted to dTTP or dUMP, dCMP, and dCMP. The conversion from dTMP to dUMP is catalyzed by thymidylate synthase (TS), and coupled with folate metabolism. TS is fused with dihydrofolate reductase (i.e., bifunctional DHFR-TS) in all apicomplexans and many other protists. Cryptosporidium DHFR-TS is one of the few enzymes that have been more thoroughly studied and pursued as a drug target (Gooze et al., 1991; Vasquez et al., 1996; O’Neil et al., 2003; Lilien et al., 2004; Anderson, 2005a, 2005b). More recently, its crystal structure has been determined, which has revealed a unique linker domain that controls the relative orientation of the DHFR and TS domains (Anderson, 2005a).
Plasmonic photothermal effect on cytotoxicity of biogenic nanostructure synthesized through Litchi chinensis Sonn.
Published in Inorganic and Nano-Metal Chemistry, 2021
It is shown from earlier research that less amount of Se can get rid of reactive oxygen species (ROS) and the repairing of damaged DNA by seleno-enzymes that results in cell protection. High concentration of ROS contributes to cell apoptosis and cancer cells get destroyed. Se acts as the new therapeutic agent for the treatment of cancer. Zero valent Selenium (Se) NPs contain a formulation of high Se density that has the potential to deliver high doses to tumor cells locally relative to other types of selenium.[14] Silver (Ag) nanoparticles have drawn significant scientific interest due to the fact that their application, such as medical imaging, delivery of drugs and antimicrobial agents. Ag is viewed as tremendous antitumor agent due to its antiproliferative and apoptosis inducing properties.[15,16] A broad spectrum anticancer drug 5-Fluorouracil (5-FU) is a pyrimidine analog used in the treatment of breast cancer and various malignancies. 5-FU interferes with DNA synthesis and acts as thymidylate synthase inhibitor. However, the clinical use of 5-FU results in significant limitations such as rapid metabolism, nonselective biodistribution, and its adverse aspects.[17,18] Evidence strongly suggests that the efficacy of 5-FU as a chemo drug in the treatment of cancer may be enhanced by a combinational approach using traditional chemo drugs or even other nontoxic plant-derived components such as genistein and curcumin.[19]
Papain bioinspired gold nanoparticles augmented the anticancer potency of 5-FU against lung cancer
Published in Journal of Experimental Nanoscience, 2020
Tong Li, Guoyue Yan, Yanyuan Bai, Mengli Wu, Gang Fang, Miao Zhang, Yangjiao Xie, Almaz Borjigidai, Biaofang Fu
The interaction of nanomaterials with the genetic material is inevitable and size-dependant. Moreover, 5-FU is an antimetabolite drug that incorporates fluoronucleotides instead of nucleotides. This interaction ultimately inhibits thymidylate synthase (TS), an enzyme involved in nucleic acid synthesis. Therefore, 5F-PpGNPs, 5-FU, and PpGNPs were found to interact with the nuclear material and cause substantial variations in the morphology and the nuclear structure of the A549 cells. The mode of cellular internalisation and, ultimately interaction with chromatin, were assessed by utilising a fluorescent dye (4′,6-diamidino-2-phenylindole) DAPI (Figure 8). The A549 cells were treated with PpGNPs, 5F-PpGNPs and 5-FU at their corresponding IC50 values for 24 h at 37 °C and stained by the DAPI dye; the untreated cells were also stained to prepare them as controls (Figure 8). The observed blue fluorescence intensities were measured under an inverted fluorescence magnifying instrument (Nikon ECLIPSE Ti-S, Japan). The apoptotic effects in comparison with the untreated cells (Figure 8A) could be easily noticed in the PpGNPs (Figure 8B), 5F-PpGNPs- (Figure 8C), and 5-FU-treated (Figure 8D) cells by observing the expanded cell membrane penetrability that produced condensed chromatin and a dark blue fluorescent consolidated nucleus. It was interesting to observe that PpGNPs also initiated apoptosis: this was further intensified by the bioconjugation of 5-FU with PpGNPs. The most critical and particular indication of the cytotoxic impact of stress is the condensation of the nucleus. The graphical representation of the observed intensities is shown in Figure 8E.
Adsorption and sensing of an anticancer drug on the boron nitride nanocones; a computational inspection
Published in Computer Methods in Biomechanics and Biomedical Engineering, 2021
Chao Wang, Lizhen Shen, Liang Wu
The widespread application of anticancer drugs has resulted in an upsurge in miscellaneous medical fields (Selvaraj and Alagar 2007). The pharmaceutical specificity of these type of drugs is of a great deal of importance regarding their critical biomedical factors (Selvaraj and Alagar 2007). 5-Fluorouracil (5FU) anticancer drug has been extensively used in chemotherapy (Selvaraj and Alagar 2007). Despite the superior applicability of 5FU, its unwanted side effects should be diminished especially by slow release of its prodrug form metal-drug complexes (Selvaraj and Alagar 2007; Hatamluyi et al. 2019). The drug delivery application of 5FU in chemotherapy and its mechanism has been widely investigated and reported in literature (Hatamluyi et al. 2019). Antineoplastic agents have played a notable role in medicine and a variety of derivatives have been applied as appropriate candidates based on their straightforward applicability and negligible side effects as main medical criteria (Hatamluyi et al. 2019). 5FU is one of conventional drugs widely applied in chemotherapeutic regimens of metastatic colorectal cancer mainly to treat solid tumors of breast and rectum (Hatamluyi et al. 2019). Mechanistically, the antitumor activity of this drug is mainly due to thymidylate synthase enzyme inhibitory effect which is needed for the proper function of RNA and DNA (Arias et al. 2008). Additionally, this drug is commonly used as an effective agent to treat colon cancer (Norouzi et al. 2009). Designing a straightforward and less complicated technique to detect 5FU in biological media is of a great deal of importance regarding large scale therapeutic application of 5FU with maximum therapeutic effects and negligible side effects. Several analytical methods of 5FU detection have been reported (Mirčeski et al. 2000). The conventional analytical detection methods of 5FU include liquid chromatography (Yang et al. 2005; Bansal et al. 2008; Pi et al. 2014), spectrofluorimetry, spectrophotometry (Sharma and Sharma 2016; Rokade and Patil 2017), and electrochemical techniques (Temerk et al. 2016; Zahed et al. 2018).