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Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Clofarabine (EvoltraTM) is a more recently introduced second-generation synthetic nucleoside analogue designed and developed in the late 1990s to be resistant to deamination by adenosine deaminase (Figure 3.10). The molecular structure is similar to cladribine but includes a fluorine atom at the C2ʹ-position of the sugar moiety. Introduced into clinical practice in 2004, this analogue inhibits both DNA polymerase and ribonucleotide reductase. It is approved for use in relapsed or refractory acute lymphoblastic leukemia in patients who have received at least two previous therapeutic regimens.
Primary Immunodeficiencies
Published in Gérard Chaouat, The Immunology of the Fetus, 2020
Alain Fischer, Durandy Anne, Claude Griscelli
Similarly, another purine metabolism disorder, purine nucleoside Phosphorylase (PNP) deficiency, provokes a progressive T-cell deficiency.2’ In addition, neurological abnormalities are often observed. PNP deficiency provokes the accumulation of deoxyguanosine triphosphate, which inhibits ribonucleotide reductase in T-lymphocytes. Rare diseases involving pyrimidine synthesis (oroticuria) folate metabolism (methionine synthase deficiency) or carboxylases (biotin-dependent multicarboxylase deficiency) can also lead on some occasions to T- and B-cell deficiencies.
Taste Modifiers and Sweet Proteins
Published in Robert H. Cagan, Neural Mechanisms in Taste, 2020
Various groups of rat chorda tympani nerve fibers have been evaluated for their response to various taste solutions, including such flavor potentiators as MSG and 5′-ribonucleotides.13,14 It was found that certain fibers responded as intensively for the flavor potentiators as for the basic taste qualities. Rats are sensitive to 5′-ribonucleotides13 and respond extremely well to low levels of this flavor potentiator. Synergism has been observed between 5′-nucleotides and all the amino acids used.15 That study showed that purine-based 5′-phosphate ribonucleotides lead to an increase in the affinity of amino acids for the respective receptor sites and have a synergistic effect on the response to amino acids. This suggests that there are specific binding sites for these nucleotides on the taste receptor membrane. The binding sites may be also part of (or very closely associated with) the amino acid receptors (see Chapter 1). On the other hand, Torii and Cagan16 showed that the number of exposed sites increases, not the affinity.
Polycythemia vera: aspects of its current diagnosis and initial treatment
Published in Expert Review of Hematology, 2023
Richard T Silver, Ghaith Abu-Zeinah
The importance of dose and duration of HU has been previously emphasized. It is not unreasonable to suggest that the use of a cytotoxic agent such as HU may predispose to increased clonal evolution, additional cytogenetic abnormalities, and the subsequent evolution to MDS or acute leukemia [22,25,65,93,94]. This is not surprising since the drug interferes with DNA synthesis owing to its inhibitory effects on ribonucleotide reductase. Its cytotoxicity affects the cell cycle specifically during the S phase. An increased incidence of genetic abnormalities is seen in vitro and in cultured cells [95]. Nevertheless, the issue of HU-induced leukemogenicity remains unresolved and contentious. Analysis of three prospective French studies of patients treated with either HU or pipobroman established HU as less leukemogenic than pipobroman but associated HU with a higher frequency of MDS/AML than previously anticipated [93]. The frequency of patients developing AML or MDS was 6.6% at 10 years, 16.5% at 15 years, and 24% at 20 years. The effect of disease duration could not be disassociated from the effect of HU. Long-term use of HU in younger patients must be a deliberate decision, especially in patients with other molecular abnormalities, with so-called ‘high-risk’ gene mutations. The finding of U2AF1, SRSF2, ASXL1, IDH1, IDH2, TP53, and other molecular abnormalities in normal individuals [96] and in patients with PV [34,97,98] is troubling as they have been associated with evolution to MDS and/or AML.
Strategies for targeting RNA with small molecule drugs
Published in Expert Opinion on Drug Discovery, 2023
Christopher L. Haga, Donald G. Phinney
Whereas proteins are composed of 20 amino acids that form complex tertiary structures, RNAs are constructed of 4 ribonucleotides. Thus far, small molecule targeting of RNAs has largely focused on identifying compounds capable of binding to secondary structural motifs. Although these structural motifs are highly specific based on their composition and ability to bind specific RNA ligands, they are also shared by numerous RNAs. Shared secondary structure motifs between RNAs is a major impediment to finding effective small molecule inhibitors against a specific RNA. Perhaps the most important problem at hand is off-target effects, where a small molecule binds to and inhibits a multitude of RNAs, rather than a single specific target. Whereas similar protein structures may bind to the same molecule, determining off-target effects for RNA-binding small molecules is complicated due to the lack of structural information available for RNAs. As described in this review, secondary structural motifs can be determined by either chemical means or through computational predictions. However, RNA transcription and splicing are highly dependent on the state and type of cell. This transcriptional variation could introduce new binding sites leading to new off-target events. Additionally, dose responses of the drugs need to be carefully determined to take into account potential new binding sites that may act as ‘sponges’ for small molecules, while minimizing off-target effects.
Targeted drug therapy in non-small cell lung cancer: Clinical significance and possible solutions-Part I
Published in Expert Opinion on Drug Delivery, 2021
Archana Upadhya, Khushwant S. Yadav, Ambikanandan Misra
Gemcitabine is a deoxycytidine analog that gets converted intracellularly to cytotoxic gemcitabine diphosphate and triphosphates. The triphosphates of gemcitabine further get incorporated into DNA and inhibit the elongation of DNA by DNA polymerase [120]. The cells, which are deficient in the nucleoside transporter protein hENT-1, are resistant to gemcitabine due to reduced intracellular transport of the drug. The regulatory subunits of the enzyme ribonucleotide reductase, RRM1 and RRM2 are involved in the metabolism of gemcitabine. Increased expression of these proteins or increased activity of these subunits decrease the sensitivity of the cells to gemcitabine [111,117,121,122]. Ribonucleotide reductase (RR) reduces ribonucleotide diphosphates to their corresponding deoxyribonucleotides, the precursors of DNA. RR is involved in DNA repair and is a rate-limiting enzyme in DNA synthesis.