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9-β-D-Arabinofuranosylguanine

  • Sophie Curbo
  • Anna Karlsson
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

9-β-D-Arabinofuranosylguanine (ara-G) was synthesized in 1964, but because of its difficult chemical synthesis and poor solubility properties, it was 1995 before a prodrug of ara-G, nelarabine, entered clinical trials. Ara-G is a deoxyguanosine analog that needs to be phosphorylated inside the cell for pharmacological activity. In the first and rate-limiting phosphorylation step, ara-G is a substrate of both the mitochondrial deoxyguanosine kinase and the cytosolic deoxycytidine kinase. Once phosphorylated to its triphosphate derivative, ara-GTP acts as a structural analog of deoxyribonucleotide 5?-triphosphate and is thereby incorporated into DNA. The accumulation of the triphosphate form of ara-G results in inhibition of DNA synthesis and subsequent cell death. Although preclinical studies have shown that ara-G has higher toxicity in T than B lymphoblasts, nelarabine has shown promising effect not only in patients with T-cell malignancies but also in patients with B-cell malignancies. Nelarabine has now earned fast track status from the US Food and Drug Administration for the treatment of T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma in those who have not responded to or whose disease has progressed during treatment with at least two standard regimens. Nelarabine is an interesting new anticancer agent that might be used as a standard treatment in the future.

Key Words

Anticancer 9-β-D-arabinofuranosylguanine deoxyguanosine analog deoxyguanosine kinase mitochondrial deoxynucleosidekinases nelarabine T-cell malignancies 

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Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Sophie Curbo
    • 1
  • Anna Karlsson
    • 1
  1. 1.Department of Laboratory Medicine, Division of Metabolic DisordersKarolinska InstitutetStockholmSweden

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