Antimetabolites
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Cladribine (LeustatTM and LitakTM) was approved in 1992 and is very similar to fludarabine in structure, except that the C2-fluorine substituent on the adenine core has been replaced with a chlorine and the C2ʹ-hydroxyl substituent on the C9-arabinofuranosyl moiety has been removed (Figure 3.10). This analogue is phosphorylated by deoxycytidine kinase to its nucleotide form, which then accumulates and becomes incorporated into DNA, ultimately causing strand breaks that lead to cell death. It is given by subcutaneous injection (i.e., LitakTM) or intravenous infusion (i.e., LeustatTM) to treat hairy cell leukemia and B-cell chronic lymphocytic leukemia. In the noncancer area it is also used to treat highly active relapsing-remitting multiple sclerosis, for which a tablet formulation is available.
Genomic Instability During Aging of Postmitotic Mammalian Cells
Alvaro Macieira-Coelho in Molecular Basis of Aging, 2017
Hydroxymethyluracil is an oxidation product of thymine, and uracil is the deamination product of cytosine. It has been suggested that deamination of deoxycytidine is a common event in the genome of a mammalian cell at 37°C.44,55,63 The work of Ames and others,132–135 moreover, has shown that oxidation damage to mammalian DNA can be extensive for some cells. Therefore, it is surprising that Kirsh et al.151 failed to detect deoxyuridine or 5-hydroxymethyldeoxyuridine in DNAs from various tissues of mice ranging in age from 7 to 31 months. The absence of altered deoxynucleosides in somatic cell DNA implies exceedingly efficient repair of these lesions. This investigation employed reversed-phase HPLC separation of deoxynucleosides, coupled with UV-detection/quantification.151 The limits of detection corresponded to approximately 10 pmol of modified deoxynucleosides per micromole of normal deoxynucleosides, or 1 modification per 105 residues. To compare this method with those that were used to measure indigenous methyl adducts128 and oxidative damage,133,135 one can estimate that UV detection is 10- to 20-fold lower than electrochemical detection, depending on the electrochemical activity of the individual base or deoxynucleoside. Therefore if background, steady-state levels of deoxyuridine and 5-hydroxymethyldeoxyuridine in DNA are similar to those for 7-methylguanine or 8-hydroxdeoxyguanosine, minimum detection limits of 1 × 10-6 will be required to measure them.
ACTIONS OF ANTI-CANCER DRUGS
James Bishop in Cancer Facts, 1999
Gemcitabine (2',2'-difluorodeoxycytidine) is another deoxycytidine analogue with multiple modes of action. As with ara-C, the activated diphosphate form is an inhibitor of ribonucleotide reductase which leads to a depletion of intracellular pools of dCTP and dATP. The triphosphate may be incorporated into DNA by the enzyme DNA polymerase followed by a futher deoxynucleotide. Gemcitabine, in this penultimate position, is resilient to exonucleases and this leads to 'masked' DNA chain elongation termination. Gemcitabine has other self-potentiating effects such as inhibiting CTP synthetase. Also, dCTP is a required cofactor for dCMP deaminase, which converts gemcitabine to the essentially inactive 2',2'-difluorodeoxyuridine. The depletion of the dCTP pools should reduce the inactivation of the drug.
RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment
Published in Expert Opinion on Investigational Drugs, 2019
Beatrice Balboni, Btissame El Hassouni, Richard J. Honeywell, Dzjemma Sarkisjan, Elisa Giovannetti, Julie Poore, Callie Heaton, Christine Peterson, Ely Benaim, Young B. Lee, Deog J. Kim, Godefridus J. Peters
According to the similarity to other cytidine-analogs, two enzymes were tested, known to be involved in cytidine and cytidine analog metabolism: UCK (Uridine-cytidine kinase in both forms UCK1 and UCK2), is responsible for the activation of Aza-CR [20], and dCK (deoxycytidine kinase) for gemcitabine and aza-CdR [21]. To analyze the contribution of these enzymes to RX-3117 metabolism, protection studies were performed with (deoxy)nucleosides, uridine, cytidine, and deoxycytidine. Deoxycytidine did not protect any of the analyzed cell lines against RX-3117, in contrast to uridine and cytidine, which were able to protect cells from RX-3117 effects in a dose-dependent manner [12]. This demonstrated that dCK was not involved in activation of RX-3117, since deoxycytidine would have reverted the sensitivity, as was found earlier for gemcitabine [22]. However, uridine and cytidine protected cells from RX-3117.
Inhibitor selectivity of CNTs and ENTs
Published in Xenobiotica, 2019
Balázs Vaskó, Viktória Juhász, Beáta Tóth, Anita Kurunczi, Zsolt Fekete, Joseph Krisjanis Zolnerciks, Emese Kis, Rémi Magnan, Axel Bidon-Chanal Badia, Marçal Pastor-Anglada, Eszter Hazai, Zsolt Bikadi, Ferenc Fülöp, Peter Krajcsi
The selectivity for the ENT2 is the reverse of that observed with CNTs, in that IC50 values of the arabinose containing compounds were smaller than IC50 values of cytosine containing compounds (Figure 5(E); Table 2). Correlation of observed IC50 values with IC50/Ki or Km values from the literature was difficult to analyze as for some interactions the published data scattered over a several log-range. We therefore, only compared data with literature data generated using the same expression system and covering at least three transporters to see if correlation in ranking was observed. IC50 values for cytidine generated in our study (381.5 µM (CNT2) > 144.7 µM (ENT1) > 15.6 µM (CNT1) > 3.6 (CNT3)) were similar and the ranking was exactly the same as in another study using a Saccharomyces cerevisiae expression system (1445 µM (CNT2) > 171 µM (ENT1) > 17 µM (CNT1) > 5 (CNT3) (Clarke et al., 2006)). Our data for gemcitabine ranked as follows: 361.2 µM (CNT2) > 42.9 (CNT3) > 20.2 µM (CNT1). Another study using again a yeast expression system yielded data that is more than threefold greater for CNT2 but the ranking is again the same: 1388 µM (CNT2) > 26 µM (CNT3) > 13 µM (CNT1) (Damaraju et al., 2012). Published 2′-deoxycytidine data from these same expression systems showed identical rankings (1714 µM (CNT2) > 9 µM (CNT1) ∼ 7 µM (CNT3)) (Clarke et al., 2006) to those observed in this study (480.5 µM (CNT2) > 17.4 µM (CNT3) ∼ 12.5 µM (CNT1)).
Notch promotes DNMT-mediated hypermethylation of Klotho leads to COPD-related inflammation
Published in Experimental Lung Research, 2018
Jie Qiu, Ya-Nan Zhang, Xiwei Zheng, Peng Zhang, Gang Ma, Hai Tan
Human bronchial epithelial (16HBE) cells and Murine alveolar macrophage cell line MH-S (CRL-2019) were obtained from American Type Culture Collection (ATCC, Manassas, VA, USA) and were maintained in RPMI-1640 medium (Thermo Fisher Scientific, Waltham, MA, USA), which were supplemented with 10% Gibco fetal bovine serum (FBS, Thermo Fisher Scientific, Waltham, MA, USA) and 1% streptomycin/penicillin/glutamate solution (Thermo Fisher Scientific, Waltham, MA, USA). The cells were cultured at 37 °C in a humidified atmosphere containing 5% CO2. Cells were reseeded with fresh RPMI-1640 complete media every two to three days. RPMI-1640 medium with 1% FBS was added to starve MH-S cells one day before the experiment. The inhibitor of DNMT, 5-Aza-2'-deoxycytidine, was purchased from Sigma-Aldrich (Sigma-Aldrich, MO, USA) and was dissolved in DMSO as concentrated stock solutions. Dual antiplatelet therapy (DAPT) and the γ-secretase inhibitors were obtained from Tocris Bioscience (Tocris Bioscience, Bristol, UK).
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