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Antimetabolites
Published in David E. Thurston, Ilona Pysz, 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.
Mechanisms of Resistance to Antineoplastic Drugs
Published in Robert I. Glazer, Developments in Cancer Chemotherapy, 2019
Philip J. Vickers, Alan J. Townsend, Kenneth H. Cowan
Since many antineoplastic agents are nucleoside analogs, phosphorylation is one of the most common mechanisms for activation of anticancer drugs. For example, phosphorylated metabolites of cytosine arabinoside (Figure 1) and 5-azacytidine represent the intracellular active forms of these drugs, which then exert their cytotoxic effects through a variety of mechanisms.23 The enzymes catalyzing the rate-limiting steps in the phosphorylation (activation) of these drugs are deoxycytidine kinase12 and uridine-cytidine kinase,14,24 respectively. A number of studies of cultured cell lines,14 clinical isolates,13 and experimental tumor models13 indicate that decreased activities of these enzymes within target cells can be responsible for resistance to both of these pyrimidine analogs.
Gastrointestinal cancer
Published in Michael JG Farthing, Anne B Ballinger, Drug Therapy for Gastrointestinal and Liver Diseases, 2019
Justin S Waters, David Cunningham
A more recently developed antimetabolite drug that is proving very useful, particularly in carcinoma of the pancreas, is gemcitabine. This is a cytidine analogue that is incorporated into DNA in its triphosphate form, after activation by deoxycytidine kinase. This results in chain termination after the addition of one further nucleotide. It also inhibits the activity of several enzymes involved in cytidine metabolism, including ribonucleotide reductase, dCMP deaminase, and CTP synthetase, and is incorporated into RNA, leading to inhibition of RNA synthesis. Cell cycle arrest occurs in the S phase followed by the induction of cell death by apoptosis.
The bone marrow stromal niche: a therapeutic target of hematological myeloid malignancies
Published in Expert Opinion on Therapeutic Targets, 2020
Lena Behrmann, Jasmin Wellbrock, Walter Fiedler
Beside the molecular interactions between niche cells, ECM and malignant cells, the metabolism of cancer cells might be a potential target for therapy as well. It is known that cancer cells switch to specialized metabolic signatures to ensure increased metabolic desires [117]. One key driver of metabolic reprogramming is hypoxia, since low oxygen induces cytoplasmic glycolysis instead of oxidative phosphorylation [118]. Cytoplasmic glycolysis has the benefit of reduced intracellular reactive oxygen species (ROS) production, leading to less oxidative stress. Remarkably, Degwert et al. presented in their study that under hypoxic conditions AML cells downregulate the cytarabine-activating enzyme deoxycytidine kinase representing a new resistance mechanisms to cytarabine in AML [119]. Therefore, hypoxia-activated prodrugs (HAPs) might have clinical implications [120]. HAPs are activated by a reaction consisting of a one electron reduction by generally ubiquitous redox cycling in the presence of oxygen. Under normoxia, the radical anion prodrug undergoes redox cycling with available oxygen leading to a relatively inert prodrug. Under hypoxic conditions, the radical has a much longer half lifetime with further fragmentation that leads to the formation of the active drug specifically in hypoxic cells. Since AML and other malignant diseases increase the number of hypoxic niches in the bone marrow, HAPs have the potential to improve patients outcome in combination with traditional therapeutics and clinical benefits are estimated [120].
An update on the safety of treating relapsing-remitting multiple sclerosis
Published in Expert Opinion on Drug Safety, 2019
Clara G. Chisari, Simona Toscano, Emanuele D’Amico, Salvatore Lo Fermo, Aurora Zanghì, Sebastiano Arena, Mario Zappia, Francesco Patti
Cladribine (Mavenclad®, approved by EMA in 2017 and by FDA in 2019) is a deoxyadenosine analog, administered per os as short course for the first days of a 28-day period and again in the second 28-day period (3.5 mg group), for two succeeding years [196]. Activated through phosphorylation, it accumulates in cells with high intracellular ratio of deoxycytidine kinase, interfering with DNA metabolism and leading to apoptosis and sustained reduction of B and T lymphocytes [197]. Recently, cladribine got approval in Europe and in the US to treat highly active RMS patients [198]. The double-blind, CLARITY study showed that cladribine 5.25mg/kg and 3.5 mg/kg reduced the relapse rate at 96 weeks compared to placebo (respectively, 58% and 55% relative reduction). The risk for 3-month sustained disability progression was also reduced by about 30% in both cladribine arms [109,199,200], with a reduction of brain atrophy as well [201].
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.