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Clofarabine: Structure, Mechanism of Action, and Clinical Pharmacology

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Chemotherapy for Leukemia

Abstract

Similar to fludarabine and cladribine, clofarabine (2-chloro-2′-fluoro-2′-deoxyarabinosyladenine) is resistant to deamination by adenosine deaminase due to the presence of a halogen group at the two position of the base. However, unlike other 2′-deoxyadenosine analogs, clofarabine also has a halogen in the sugar that prevents cleavage of the glycosidic bond by purine nucleoside phosphorylase. The cytotoxic activity of clofarabine is due to both its inhibition of ribonucleotide reductase and its efficient incorporation in DNA, where it inhibits DNA synthesis. While some activity has been observed in lymphoid malignancies, clinical efficacy has primarily been observed in acute leukemias. The recommended dose of clofarabine for adult acute leukemia (40 mg/m2/day × 5 days) results in plasma levels of around 1 μM. The accumulation of clofarabine triphosphate in circulating leukemia cells is dose dependent, with a long half-life. This is particularly the case in responders, resulting in incremental increases in clofarabine triphosphate with every daily infusion of the drug. The actions of clofarabine triphosphate on ribonucleotide reductase and incorporation in the DNA repair patch suggest that a mechanism-based combination with arabinosylcytosine and DNA-damaging agents would be effective. Combination clinical trials have been conducted, while new trials are underway.

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Acknowledgments

The authors thank Hima Vangapandu, PhD, for her help with the references. The authors also thank Ms. Ann Sutton for scientific editing.

Conflict of Interest

Clofarabine was discovered at Southern Research Institute, which receives licensing fees and royalty payments from its commercial development. Some of this money is distributed to Dr. Parker. Dr. Gandhi has no conflicts of interest to disclose.

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Authors and Affiliations

  1. PNP Therapeutics, Inc., Birmingham, AL, USA

    William B. Parker

  2. Department of Experimental Therapeutics and Leukemia, The University of Texas MD Anderson Cancer Center, 301429, 1515 Holcombe Blvd, Houston, TX, 77230-1429, USA

    Varsha Gandhi

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  1. William B. Parker
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  2. Varsha Gandhi
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Correspondence to Varsha Gandhi .

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Editors and Affiliations

  1. University of Fukui, Fukui, Japan

    Takanori Ueda

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Parker, W.B., Gandhi, V. (2017). Clofarabine: Structure, Mechanism of Action, and Clinical Pharmacology. In: Ueda, T. (eds) Chemotherapy for Leukemia. Springer, Singapore. https://doi.org/10.1007/978-981-10-3332-2_16

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  • DOI: https://doi.org/10.1007/978-981-10-3332-2_16

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