Genomic Instability During Aging of Postmitotic Mammalian Cells
Alvaro Macieira-Coelho in Molecular Basis of Aging, 2017
A different type of approach to study the role of somatic mutations in the aging process is to use nucleoside or base analogs in developing rodents.247,248 The thymidine analog, 5-bromo-2′-deoxyuridine (BrdUrd), can be incorporated into replicating DNA and base pair normally with adenosine. Less frequently, the tautomeric enol form of BrdUrd can base pair with guanosine, giving rise to a transition mutation.249 BrdUrd is not a known substrate for DNA repair and persists for long periods in vivo.250 Model shuttle vector systems have shown a high degree of sequence specificity for BrdUrd-induced GC to AT transitions.251 Anisimov and Osipova247 and Craddock248 have observed a dose-dependent reduction in the mean life span of neonatal rats treated with BrdUrd. BrdUrd administration led to substantial increases in the frequency of chromosomal aberrations and sister chromatid exchanges in dividing cells. The data could be interpreted as support for the somatic mutation theory of aging. However, the available evidence can not rule out the possible role of toxic, epigenetic, or metabolic effects in shortening the life span, and somatic mutation frequencies in postmitotic cells have not been assessed.247,248
Antimetabolites
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
The combination therapy trifluridine/tipiracil (LonsurfTM), originally developed by Taiho Pharmaceutical Co. Ltd, is the most recent pyrimidine antimetabolite therapy to be introduced, approved by the FDA in February 2019 (Figure 3.11). It is a fixed combination of trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase (TPase) inhibitor that enhances trifluridine concentrations. Trifluridine (also called trifluorothymidine or TFT) was originally developed as an anti-herpes antiviral agent, primarily for the eye and was approved for medical use in 1980 sold under the trade name ViropticTM by (the then) Glaxo Wellcome. The design concept was based on the hypothesis that, as a modified form of deoxyuridine similar enough to be incorporated into viral DNA replication, the –CF3 group added to the uracil ring should block viral DNA base pairing, thus interfering with replication.
Microparticulate Carriers as a Therapeutic Option in Regional Cancer Therapy: Clinical Considerations
Neville Willmott, John Daly in Microspheres and Regional Cancer Therapy, 2020
The pharmacokinetic principles underlying embolization have been confirmed in animal and human studies. Regional advantage is reflected in diminished systemic toxicity and encouraging tumor responses. There is little evidence of increased local toxicity in most studies, although target organs are subjected to intensified treatment compared with systemic therapy. Whether response rates are superior to those achievable with conventional systemic chemotherapy or external beam radiotherapy remains open to debate because there have been so few randomized controlled trials. Furthermore, it is not known if improved tumor response equates with prolonged survival. Lessons may be learned from experience with hepatic arterial chemotherapy for colorectal metastases in which the survival advantage is equivocal. Thus, in a prospective randomized trial (69 patients) to compare intra-arterial 5-fluoro-2′-deoxyuridine (floxuridine) with systemic 5-FU, despite a significantly higher response rate in the liver with regional chemotherapy (48% versus 21%), no survival advantage was seen.47 However, in a similar study (166 patients), hepatic arterial chemotherapy with 5-fluoro-2′-deoxyuridine conferred a statistically significant survival advantage.48
Apoptosis in Primary Hyperparathyroidism
Published in Journal of Investigative Surgery, 2018
Oliwia Anna Segiet, Łukasz Mielańczyk, Adam Piecuch, Marek Michalski, Szczepan Tyczyński, Marlena Brzozowa-Zasada, Mariusz Deska, Romuald Wojnicz
Several studies revealed that apoptosis was increased in lesions of parathyroid glands compared with normal controls. Apoptotic index, measured with the use of Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL), was under 2% in PA and MGD, and under 3% of cells in PC [27]. This method reveals degradation of DNA in nuclei of apoptotic cells with the use of secondarily labeled deoxyuridine triphosphate (dUTP), which is added at the 3' OH ends of DNA fragments. Apoptotic cells were found in 85% of PA [28, 29]. Another method for assessing the process of apoptosis is single-stranded DNA (ssDNA) detection. PA, PC, and secondary hyperplasia demonstrated increased apoptosis compared with MGD, whereas normal healthy tissue showed lower apoptotic index than all parathyroid lesions [30].
Levels of Folate and Vitamin B12, and Genetic Polymorphisms Involved in One-Carbon Metabolism May Increase the Risk of Cervical Cytological Abnormalities
Published in Nutrition and Cancer, 2022
Nayara Nascimento Toledo Silva, Ana Carolina Silva Santos, Maria de Fátima Dias de Sousa Brito, Diama Bradha Andrade Peixoto do Vale, Cláudia Martins Carneiro, Angélica Alves Lima
TS enzyme catalyzes the conversion of deoxyuridine monophosphate (dUMP) into deoxythymidine monophosphate (dTMP), through methylene transfer from folate, being the only de novo source of thymidine for DNA synthesis and repair. TS acts as a protein that binds to RNA for translation repression of its messenger RNA (mRNA) or other proteins, and can regulate cell cycle progression (15, 16). High levels of TS activity may to increase DNA synthesis, as well as the accumulation of genetic alterations, due to imbalance of deoxyribonucleotide triphosphates (dNTPs) pool. Therefore, TS enzyme is a potential target of several chemotherapeutic agents in treatment of cancer, besides the analysis of its levels to be useful in evaluation of tumor cell sensitivity to radiation (17). Many polymorphisms in untranslated regions (UTRs) were identified in TS gene, which is located on chromosome 18p11.32. The polymorphisms most frequently studied are double or triple 28 bp tandem repeat in 5′-untranslated enhanced region (TSER), and 6 bp deletion/insertion at nucleotide 1494 in TS 3′-untranslated region (TS3’UTR). These two genetic variations may influence the TS gene expression and the stability of its mRNA, respectively (15).
The discovery of novel antivirals for the treatment of mpox: is drug repurposing the answer?
Published in Expert Opinion on Drug Discovery, 2023
Ahmed A. Ezat, Jameel M. Abduljalil, Ahmed M. Elghareib, Ahmed Samir, Abdo A. Elfiky
For more than a half-century, a group of deoxyuridines analogs has been known for their antiviral potential against DNA viruses. 5-substituted 2´-deoxyuridine analogs are the most important among these analogs. Three 5-substituted 2́-deoxyuridine derivatives (idoxuridine, trifluridine, and brivudine) have been approved as antiviral drugs that inhibit viral DNA biosynthesis [43]. These drugs required a phosphorylation reaction before exerting their inhibitory effect. Both idoxuridine and trifluridine are activated by cellular kinases to the 5́-triphosphate or the 5́-monophosphate forms, respectively, while Brivudine is phosphorylated to mono- or diphosphate forms by viral thymidine kinase. Idoxuridine and trifluridine are approved for keratitis caused by herpes simplex virus as topical medications.
Related Knowledge Centers
- Antiviral Drug
- Chemical Compound
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- Iodine
- Nucleoside
- Trifluridine
- Uracil
- Idoxuridine
- Base Pair
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