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Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Hydroxycarbamide (HydreaTM), also known as hydroxyurea, is an orally active agent first synthesized in the 1860s (Figure 3.14). Its antitumor activity, which was discovered much later, is thought to be due to inhibition of ribonucleotide reductase by quenching the tyrosyl radical and causing depletion of the deoxynucleoside triphosphate pool, thus blocking DNA synthesis and repair at the G1-S interface. Structures of the clinically used ribonucleotide reductase inhibitor hydroxycarbamide (HydreaTM), and triapine and tezacitabine, which are no longer in development.
Choroid Plexus Tumors and Meningiomas
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Kenneth K. Wong, Elwira Szychot, Jennifer A. Cotter, Mark Krieger
Hydroxyurea, a ribonucleotide reductase inhibitor, offered initial promise in a small case series in which a positive radiologic response was achieved in 3 of 4 patients with recurrent meningioma. However, subsequent studies of hydroxyurea showed that patients usually display a stable response, followed by progressive disease. The median progression-free survival on hydroxyurea may range from 2 to 77 months.187–189
Gallium and Other Main Group Metal Compounds as Antitumor Agents
Published in Astrid Sigel, Helmut Sigel, Metal Ions in Biological Systems, 2004
Michael A. Jakupec, Bernhard K. Keppler
Due to its inability to shift between the trivalent and a divalent oxidation state as well as certain aspects of its coordinative behavior, gallium is not incorporated into heme-iron-containing proteins such as hemoglobin or cytochromes, but it is able to compete for iron binding sites on Fe3+-dependent enzymes such as ribonucleotide reductase. Enzymatic reduction of ribonucleotides to deoxyribonucleotides is the rate-limiting step in DNA synthesis. The enzyme is highly activated in proliferating tumor cells and is thus an excellent target for tumor chemotherapy. The activity of this enzyme is dependent on a tyrosyl free radical which is located in the R2 subunit and stabilized by ferric iron but destabilized in cells exposed to transferrin-bound gallium [103,104]. This spectroscopically detectable destabilization may in part be explained by the decreased intracellular iron availability, but cell-free experiments have demonstrated that gallium is also able to interact directly with the enzyme [105], and immunoprecipitation studies suggest that gallium indeed displaces iron from the R2 subunit [106]. Consistent with this mode of action, gallium causes a reduction of ribonucleoside flow into the dTTP pool and DNA as compared to that of deoxyribonucleosides and a reduction of dNTP pools, similar to the effect of the well-known ribonucleotide reductase inhibitor hydroxyurea [103,107].
Targeting translesion synthesis (TLS) to expose replication gaps, a unique cancer vulnerability
Published in Expert Opinion on Therapeutic Targets, 2021
Sumeet Nayak, Jennifer A. Calvo, Sharon B. Cantor
DNA replication is fundamental to the propagation of all life forms and its integrity is critical for heredity and genome stability [1,2]. Accordingly, dysregulated replication invariably generates DNA mutations and/or chromosomal instability. Moreover, defects in replication proficiency are associated with premature aging and cancer [3,4]. To maintain genome integrity, DNA replication employs a dynamic process that readily responds to a range of DNA perturbations, generally described as replication stress (RS) [5]. RS derives from endogenous metabolic byproducts such as aldehydes, oxygen and nitrogen free radicals that modify DNA bases, or from environmental sources such as ultraviolet (UV) light or chemotherapies that modify DNA structure with adducts or crosslinks which, if left unrepaired, leads to DNA damage [5]. DNA replication is also challenged by insufficient building blocks, which occurs by depletion of nucleotides, for example,when cells are treated with the ribonucleotide reductase inhibitor, hydroxyurea (HU) or when cells are prematurely driven into S phase [6,7]. Additional sources of stress include DNA secondary structures that impede DNA replication, such as G-quadruplexes (G4), common fragile sites (CFS) or loop formations occurring in highly repetitive sequences such as microsatellites [8–12].
The advantages and risks of ruxolitinib for the treatment of polycythemia vera
Published in Expert Review of Hematology, 2020
Gioia Colafigli, Emilia Scalzulli, Sara Pepe, Alessio Di Prima, Fabio Efficace, Maurizio Martelli, Robin Foà, Massimo Breccia
According to the ECLAP consensus, all patients, regardless of the risks at presentation, should receive anti-platelet agents (low-dose aspirin) to reduce the rate of cardiovascular events [12]. In patients with extreme thrombocytosis at presentation (>1000 x 109/L), aspirin should be used with caution, considering the risk of an acquired Von Willebrand disease. The most commonly used cytoreductive treatment is hydroxyurea (HU), a ribonucleotide reductase inhibitor: the PV study group reported that HU is able to reduce the rate of thrombotic events when compared to phlebotomies [13]. Even if associated with a number of side effects, the most important being the mucocutaneous ulceration, large trials have failed to demonstrate the potential risk of an increased leukemogenesis [14].
Pharmacotherapeutic options for atypical meningiomas
Published in Expert Opinion on Pharmacotherapy, 2019
Syed Ali Ahsan, Kassem Chendeb, Christos Profyris, Charles Teo, Michael E. Sughrue
Hydroxyurea is a ribonucleotide reductase inhibitor that induces apoptosis in cells by blocking them off in the S phase [32,33]. Whilst it is currently one of the accepted forms of treatment by the brain tumor guidelines it has only produced a small radiographic response in some patients and has failed to show any significant clinical efficacy [34,35]. Chamberlain and Johnston conducted a retrospective case series on 60 patients with grade I recurrent meningiomas with hydroxyurea following surgery and radiotherapy [36]. The hydroxyurea showed very limited activity, this result is generalizable to atypical meningiomas due to the similar histology of recurrent grade I meningiomas and atypical meningiomas. A 2002 study looked at the effects of hydroxyurea on 20 patients with recurrent or unresectable meningiomas (3 atypical meningiomas, 1 malignant and 16 benign); hydroxyurea showed some disease stabilization in the benign group but neuroimages showed progression in the atypical and malignant group [37].