title: 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.
authors.affiliation: Department of Leukemia, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. hadyghanem@hotmail.com
authors.forename: Hady
authors.initials: H
authors.lastname: Ghanem
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Varsha
authors.initials: V
authors.lastname: Ghandhi
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
mesh_terms: D000227:Adenine Nucleotides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D000077866:Clofarabine; D003561:Cytarabine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008232:Lymphoproliferative Disorders / Q000188:drug therapy
chemical_list: D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D003561:Cytarabine; D000077866:Clofarabine