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Antimetabolites
Published in David E. Thurston, Ilona Pysz, 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.
Monographs of Topical Drugs that Have Caused Contact Allergy/Allergic Contact Dermatitis
Published in Anton C. de Groot, Monographs in Contact Allergy, 2021
Idoxuridine is a iodinated analog of deoxyuridine, with antiviral activity against Herpes simplex virus (HSV) and potential radiosensitizing activities. In chemical structure idoxuridine closely approximates the configuration of thymidine, one of the four building blocks of DNA, the genetic material of the Herpes virus. As a result, idoxuridine is able to replace thymidine in the enzymatic step of viral replication or ‘growth’. The consequent production of faulty DNA results in a pseudostructure which cannot infect or destroy tissue. Idoxuridine is indicated for use in keratoconjunctivitis and keratitis caused by herpes simplex virus. Formerly, the drug has been used in ointments and creams for the treatment of herpes labialis (cold sore), but these were soon found to be ineffective (1).
Sleep-Promoting Substance (SPS) and Nucleosides
Published in Shojiro Inoué, Biology of Sleep Substances, 2020
It has been found that no nucleosides, except for deoxyuridine, exhibited a somnogenic activity comparable to that of 10 pmol of uridine. Deoxyuridine (see Figure 14, left) caused a significant increase in SWS during the dark period. The increase was due largely to the increased occurrence of SWS episodes, but not to their prolongation. PS showed a rise, but the difference was insignificant because of large individual variations. Deoxyuridine, however, required a dose tenfold greater than uridine.
RGS7 silence protects palmitic acid-induced pancreatic β-cell injury by inactivating the chemokine signaling pathway
Published in Autoimmunity, 2023
Yurong Zhu, Jun Li, Tao Ba, Yuan Sun, Xiangyun Chang
The cell proliferation was analyzed by using the 5-ethynyl-2′- deoxyuridine (EdU) Cell Proliferation Kit (C0078S, Beyotime). Beta-TC-6 and Min6 cells (2 × 104 cells/well) were cultured in 24-well plates overnight. Cells were incubated with EdU solution (20 μM) for 2 h. Subsequently, 4% paraformaldehyde was added for 15 min at room temperature. After incubating with PBS for 10–15 min at room temperature, cells were incubated with endogenous peroxidase blocking solution for 20 min to inactivate endogenous peroxidase. After three times wash with PBS, 4′,6-diamidino-2-phenylindole (DAPI) was added and incubated for 10 min in a dark room at room temperature to stain cell nuclei. Finally, EdU-positive cells were observed and counted with a fluorescence microscope. All the experiments were performed in triplicate.
Exploiting active nuclear import for efficient delivery of Auger electron emitters into the cell nucleus
Published in International Journal of Radiation Biology, 2023
Andrey A. Rosenkranz, Tatiana A. Slastnikova, Mikhail O. Durymanov, Georgii P. Georgiev, Alexander S. Sobolev
It is known that AE-emitting radiopharmaceuticals can also exert effects on the regulatory pathways and mediate cell death (Paillas et al. 2016). A modulation of these regulatory pathways could be interesting as a possible target in radionuclide therapy. However, the direct cytotoxicity of 125I was significantly higher with intranuclearly accumulating 5-[125I]Iodo-2′-deoxyuridine than in the case of activation of these regulatory pathways (Paillas et al. 2016). Generally, regulatory pathways as the main targets in radionuclide therapy do not appear to be the best way to treat diseases. There are several intersecting intracellular regulatory pathways, which are often specific for certain cell types and patients. Therefore, predicting the therapeutic effects may be sophisticated. The destructive effects on the nuclei of cancer cells, which result in their death due to damage to unique DNA molecules, appears to be a more reliable way to treat cancer using radionuclide therapy.
An overview of ProTide technology and its implications to drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Michaela Serpi, Fabrizio Pertusati
A significant breakthrough was the application of the ProTide technology to 5-fluoro-2ʹ-deoxyuridine (FUdR), which led to substantial increases in in vitro cancer cell cytotoxic in comparison to the parent drug [29]. Among several FUdR ProTides the naphthyloxy L-alanine benzyl ester derivatives (NUC3373, 9) (Figure 3) was identified as lead candidate by NuCana plc. Whereas FUdR substantially lost its cytostatic potential in thymidine kinase (TK)-deficient cell cultures, NUC3373 markedly kept its antiproliferative activity in TK-deficient tumor cells. The prodrug is largely independent from the intracellular TK activity to exert its cytostatic action. NUC3373 was found to inhibit TS in the TK-deficient and wild-type cell lines at drug concentrations that correlated well with its cytostatic activity in these cells. NUC3373 does not seem to be susceptible to inactivation by catabolic enzymes such as thymidine phosphorylase (TP) and uridine phosphorylase (UP). NUC3373 is currently evaluated in a phase I study in patients with advanced solid tumors and in a phase Ib in combination with other agents typically administered with fluorouracil (5-FU; drug used as standard therapy) in patients with advanced colorectal cancer [97]. The preliminary results of phase I study showed that NUC3373 has a favorable pharmacokinetic and safety profiles with respect to 5-FU [98].