Mechanisms of Resistance to Antineoplastic Drugs
Robert I. Glazer in Developments in Cancer Chemotherapy, 2019
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.
Telbivudine
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Telbivudine, like other nucleoside and nucleotide analogs, is a prodrug that must be phosphorylated intracellularly before it is active. Telbivudine is phosphorylated by cellular kinases to the active telbivudine 5′-triphosphate, which has an intracellular half-life of 14 hours (Standring et al., 2001). Deoxycytidine kinase (dCK) and thymidine kinase (Semizarov et al., 1997) have been implicated in the phosphorylation of telbivudine. The active triphosphate inhibits the HBV polymerase by competing with the natural substrate, deoxythymidine 5′-triphosphate (dTTP). Incorporation of telbivudine 5′-triphosphate into viral DNA causes DNA chain termination and irreversible inhibition of viral replication. Telbivudine inhibits both first- and second-strand DNA synthesis by the HBV polymerase, but preferentially inhibits synthesis by the second-strand HBV DNA (Seifer et al., 2005). Telbivudine 5′-triphosphate at concentrations ≤ 100 micromolar did not inhibit human cellular DNA polymerases alpha, beta, or gamma (Standring et al., 2001).
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.
Pharmacological strategies to overcome treatment resistance in acute myeloid leukemia: increasing leukemic drug exposure by targeting the resistance factor SAMHD1 and the toxicity factor Top2β
Published in Expert Opinion on Drug Discovery, 2021
Nikolas Herold
Ara-C is an analogue to deoxycytidine and uses the same transmembrane transport protein (hENT1) before being activated to ara-CTP, incorporated into DNA, and causing DNA damage. Clinical resistance is associated with low intraleukemic levels of ara-CTP (for review, see [19]). Deoxycytidine kinase (dCK) is the rate-limiting enzyme for the synthesis of ara-CTP. Even though down-regulation of dCK in cell lines can lead to ara-C resistance, there was no evidence for this to happen in patients. Cellular phosphatases that can reverse phosphorylation are therefore the likeliest culprit for differential ara-CTP accumulation in AML. One of these phosphatases, cytosolic nucleotidase-II (NT5C2), can acquire activating mutations that lead to resistance to a variety of antimetabolites, even though those mutations have thus far only been reported for acute lymphoblastic leukemia. Furthermore, several studies suggested that high expression of NT5C2 correlated with worse clinical outcome in AML, at least when combined with the expression levels of dCK (for review see [19]:). Unfortunately, no potent cell-active inhibitor of NT5C2 exists.
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.
CD8+ cytotoxic T cell responses to dominant tumor-associated antigens are profoundly weakened by aging yet subdominant responses retain functionality and expand in response to chemotherapy
Published in OncoImmunology, 2019
Connie Jackaman, Joanne K. Gardner, Federica Tomay, Joshua Spowart, Hannah Crabb, Danielle E. Dye, Simon Fox, Stephen Proksch, Pat Metharom, Satvinder S. Dhaliwal, Delia J. Nelson
We then examined the effect of two chemotherapeutics agents on young versus elderly tumor-bearing mice. Cisplatin and gemcitabine display clinical activity against a range of solid tumors including mesothelioma. Cisplatin, a platinum-containing drug, uses transporter molecules to enter cells, bind DNA and interfere with transcription and/or DNA replication, triggering cytotoxic activity and cell death. Gemcitabine, a prodrug activated by deoxycytidine kinase and other kinases into gemcitabine triphosphate, has multiple intracellular targets and can be incorporated into RNA and DNA by competing with deoxycitidine triphosphate to induce cell death. We have previously shown that both chemotherapies enhance CTL activity against subdominant epitopes in young tumor-bearing mice.15
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