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Lipid Nanocarriers for Oligonucleotide Delivery to the Brain
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Andreia F. Jorge, Santiago Grijalvo, Alberto Pais, Ramón Eritja
The antitumoural action of the decamer FdU10 composed by 10 monomers of 5-fluoro-2/-deoxyuridine monophosphate (FdU) has been demonstrated in in vivo preclinical models of acute myeloid leukaemia [93], acute lymphocytic leukaemia [94], prostate cancer [95] and GBM [96]. Once internalised, the metabolites of the polymeric fluoropyrimidine drug bind covalently to the nucleotide-binding site of thymidylate synthase (TS), inhibiting in this way the synthesis of deoxythymidine monophosphate (dTMP) and, consequently, triggering an apoptosis mechanism called ‘thymineless cell death’ [97]. FdU10 has displayed minimal penetrance of the BBB, but through intracerebral administration, it has been demonstrated to be safe and efficient in reducing tumour progression [96]. Histological analyses revealed almost complete suppression of tumours in a GBM mouse orthotopic xenograft model. Of note, recently DNA nanoassemblies were designed to hide in scaffold polymeric fluoropyrimidine strands, representing a promising approach for cancer therapy [98, 99].
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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].
Cancer/Anti-Cancer Chemotherapy: Pharmacological Management
Published in Mihai V. Putz, New Frontiers in Nanochemistry, 2020
Bogdan Bumbăcilă, Corina Duda-Seiman, Daniel Duda-Seiman, Mihai V. Putz
Thymidylate synthetase (TS) is an enzyme that catalyzes the biotransformation of deoxyuridine monophosphate to deoxythymidine monophosphate. Thymidine is one of the nucleotides present in DNA structure.
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).
DNA methylation modifications induced by hexavalent chromium
Published in Journal of Environmental Science and Health, Part C, 2019
Xinnian Guo, Lingfang Feng, Bernardo Lemos, Jianlin Lou
Global DNA methylation plays an important role in many chemical carcinogenesis including in vitro, in vivo and population studies.43–46 Labra et al. evaluated genetic damage and epigenetic alteration induced by potassium dichromate in Brassica napus L. They found increased global DNA methylation in the CCGG-DNA sequence after treatment of 10–200 mg/l potassium dichromate in B. napus L, and the methylation levels were positively correlated to potassium dichromate concentration. The global DNA hypermethylation of plants might be associated with plant self-protection mechanisms, which induced cell cycle arrest with the consequent reduction of plant growth and development.26 Another study investigating workers in a chromate plant found that chronic occupational chromate exposure could induce folate depletion in conjunction with its action as a direct mutagen. Exposure resulted in further reduced thymidylate synthesis and nucleotide imbalance and DNA disintegrity, and finally accelerated double-strand DNA breaks, genetic instability, and chromosome fragility.27–29 In our previous study, a human B lymphoblastoid cell line and a human lung cell line A549 were exposed to 5–15 µM potassium dichromate and 1.25–5 µg/cm2 lead chromate for 2–24 hours. Our results showed that both of Cr (VI) compounds resulted in global DNA hypomethylation followed by cell cycle arrest at G1 phase in both cell lines.47 We suggested that the decreased methylation level of global DNA might be associated with cell cycle arrest induced by Cr (VI).47 We also studied the effect of hexavalent chromium on DNA methylation in Sprague-Dawley rats after being exposed to potassium dichromate through drinking water for 4 weeks. The results showed that oral ingestion of hexavalent chromium through drinking water caused global DNA hypomethylation in genomic DNA extracted from whole blood of male rats, and a good correlation was found between increased MDA levels and reduced global DNA methylation.48 MDA concentration has been measured to examine oxidative stress and as an indicator of oxidative imbalance during the onset of many diseases.49 It is estimated that Cr (VI) could induce global DNA hypomethylation through oxidative stress and then further contribute to the development of diseases.