Clofarabine in leukemia

Abstract

Clofarabine is a second-generation purine nucleoside analogue that has been synthesized to overcome the limitations and incorporate the best qualities of fludarabine and cladribine. Clofarabine acts by inhibiting ribonucleotide reductase and DNA polymerase, thereby depleting the amount of intracellular deoxynucleoside triphosphates available for DNA replication. Compared with its precursors, clofarabine has an increased resistance to deamination and phosphorolysis, hence better stability, as well as higher affinity to deoxycytidine kinase (dCyd), the rate-limiting step in nucleoside phosphorylation. In 1993, the first Phase I study was initiated in patients with hematologic and solid malignancies. Since then, clofarabine has demonstrated single-agent antitumor activity in pediatric and adult acute leukemia. Owing to its unique properties of biochemical modulation when used in combination with other established antileukemic drugs, mainly cytarabine, combination regimens containing clofarabine are being evaluated. A review of the English literature was performed that included original articles and related reviews from the MEDLINE (PubMed) database and from abstracts based on the publication of meeting materials. This article describes the development, pharmacology and clinical activity of clofarabine, as well as its emerging role in the treatment of acute leukemia, myelodysplastic syndrome and solid tumors.

Cladribine, But Not Fludarabine, Added to Daunorubicin and Cytarabine During Induction Prolongs Survival of Patients With Acute Myeloid Leukemia: A Multicenter, Randomized Phase III Study

“…The survival advantage was probably mainly a consequence of improved CR rate because no difference could be demonstrated with respect to LFS. 37 Our study was not powered to search for differences between treatment arms in specific subgroups of patients. Interestingly, the subgroup that appeared to benefit most from DAC induction was patients age 50 years or older (ie, those frequently considered ineligible for myeloablative alloHSCT).…”

The discovery of purine-based agents targeting triple-negative breast cancer and the αB-crystallin/VEGF protein–protein interaction

“…In recent years, our laboratory has focused on the discovery of new drug candidates for potential application in the TNBC setting (Chen et al 2014;Haynes et al 2016). As part of these efforts, we were attracted to the possibilities associated with purine-based compounds, given their long and distinguished history in cancer drug development, including clinically approved anti-leukaemia drugs such as fludarabine (Rodriguez 1994) and clofarabine (Ghanem et al 2010). Purines represent a privileged heterocycle in drug design, given the ability of purine analogues to bind tightly within hydrophobic folds and inhibit a range of key enzyme targets, such as members of the diverse protein kinase, sulfatase and phosphorylase families.…”

The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: the electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases

“…Pyrimidine and purine 2-deoxy-2-fluoro-β-D-arabinofuranosides demonstrate a broad spectrum of biological activity [1–9] and are valuable constituents of artificial oligonucleotides of great molecular biological and medicinal potential [10–11]. Among this family of nucleosides 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-2-chloroadenine ( 1 ; clofarabine) has recently attracted a lot of attention owing to its successful application for the treatment of pediatric acute leukemia [5–9].…”

“…Among this family of nucleosides 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-2-chloroadenine ( 1 ; clofarabine) has recently attracted a lot of attention owing to its successful application for the treatment of pediatric acute leukemia [5–9]. As might be expected, a great number of publications are devoted to the synthesis of clofarabine.…”