Fludarabine | DNA biosynthesis inhibitor

Fludarabine (21679-14-1) is a synthetic adenosine analog that inhibits DNA biosynthesis and is a clinically useful antineoplastic agent.¹ In cells fludarabine accumulates as its 5’-triphosphate (F-ara-ATP) for which the rate-limiting step in formation is the conversion of fludarabine to its monophosphate.² F-ara-ATP has multiple mechanisms of action including inhibition of ribonucleotide reductase, DNA polymerase, ligase and primase.² A frequently used agent in myeloablative conditioning regimens for allogeneic hematopoietic cell transplantation.³ Immunosuppressive effects are mediated via inhibition of TNFa-stimulated production of IL-2 and IFN-g through inactivation of NFkB.⁴ Antagonist at adenosine A1 receptors.⁵

References:

1. Ross et al. (1993), A review of its pharmacological properties and therapeutic potential in malignancy; Drugs, 45 737
2. Gandhi and Plunkett (2002), Cellular and clinical pharmacology of fludarabine; Pharmacokinet. 41 93
3. Langenhorst et al. (2019), Fludarabine exposure in the conditioning prior to allogeneic hematopoietic cell transplantation predicts outcomes; Blood Adv., 3 2179
4. Nishioka et al. (2008), Fludarabine induces growth arrest and apoptosis of cytokine- or alloantigen-stimulated peripheral blood mononuclear cells and decreases production of Th1 cytokines via inhibition of nuclear factor kappaB; Bone Marrow Transplant., 41 303
5. Jensen et al. (2012), Cytotoxic purine nucleoside analogues bind to A1, A2A and A3 adenosine receptors; Naunyn Schmiedebergs Arch. Pharmacol., 385 519