Clofarabine in the treatment of acute myeloid leukaemia and acute lymphoblastic leukaemia: a review.
Clofarabine, a synthesised adenosine nucleoside, has recently demonstrated single-agent activity in the acute leukaemias. Originally developed to capture the best qualities of cladribine and fludarabine, clofarabine contains halogenated carbons, rendering it resistant to inactivating enzymes and maintaining its stability in acidic environments. Like other adenosine nucleosides, clofarabine acts by inhibiting ribonucleotide reductase and DNA polymerase, thereby depleting the amount of intracellular deoxynucleoside triphosphates available for DNA replication and also resulting in premature DNA chain termination. Clofarabine has also been shown to induce apoptosis in transformed cell lines, indicating that clofarabine results in cell death in both cycling and non-cycling cells. Interest in the development of clofarabine was initially hampered by the availability of other active nucleoside analogues for the treatment of haematological malignancies. However, the results of several early-phase trials evaluating the use of clofarabine in acute leukaemias in adults and children have rekindled enthusiasm for further investigation into its use. This article describes the development, pharmacology, toxicity and clinical activity of clofarabine, as well as discuss its potential role in the treatment of acute leukaemia.
Kline
Justin P
JP
Department of Medicine, Cancer Research Center, University of Chicago, Chicago, IL, USA. jkline@medicine.bsd.uchicago.edu
Larson
Richard A
RA
D000227:Adenine Nucleotides / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077866:Clofarabine; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000453:epidemiology / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000453:epidemiology / Q000378:metabolism
D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D000077866:Clofarabine