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Lipophilic 1-β-d-arabinofuranosyl cytosine derivatives in liposomal formulations for oral and parenteral antileukemic therapy in the murine L1210 leukemia model

  • Original Paper
  • Experimental Oncology
  • Published:
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Abstract

TheN 4-alkylcytosine arabinoside derivativeN 4-octadecyl-AraC (AraC-Ocd, NOAC) and the (1-octadecylglycero-3-phospho)-AraC (Ocd-GroP-AraC, OPA) conjugate are new lipophilic derivatives of the cytostatic drug 1-β-d-arabinofuranosylcytosine (AraC) that produce high antileukemic effects in the L1210 murine leukemia model when administered orally or parenterally as liposomal formulations. Between 83% and 100% of the treated animals were cured after five consecutive daily oral drug applications with a total dose of 1 mmol/kg AraC-Ocd or Ocd-GroP-AraC. Corresponding results were obtained after parenteral therapy on days 2 and 6 after tumor inoculation with five- to ten-fold lower concentrations of these two compounds. A comparable cytotoxic activity was found with the orally active AraC-5′-(n-stearyl phosphate). However, because of its strong hemolytic toxicity this derivative cannot be used for parenteral therapy. Another AraC conjugate, which was modified with two long-chain hydrocarbons, the (1-octadecylglycero-3-phospho)-N 4-hexadecyl-AraC was, probably because of poor oral bioavailability, only active when applied parenterally. The new lipophilic AraC derivatives AraC-Ocd and Ocd-GroP-AraC are compounds with a high potential for the oral treatment of leukemias and possibly also of solid tumors.

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Abbreviations

AraC :

1-β-d-arabinofuranosylcytosine

AraC-Ocd :

N 4-octadecyl-1-β-d-arabinofuranosylcytosine

Ocd-GroP-AraC :

5′-O-(1-octadecyl-rac-glycero-3-phospho)-1-β-d-arabinofuranosylcytosine

OcdP-AraC :

1-β-d-arabinofuranosylcytosine-5′-(n-stearylphosphate)

Ocd-GroP-AraC-Hxd :

5′-O-(1-octadecyl-rac-glycero-3-phospho)-N 4-hexadecyl-1-β-d-arabinofuranosylcytosine

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Authors and Affiliations

  1. Department of Pathology, Division of Cancer Research, University Hospital, CH-8091, Zürich, Switzerland

    R. A. Schwendener

  2. Institute of Organic Chemistry, University of Tübingen, D-72076, Tübingen, Germany

    H. Schott

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  1. R. A. Schwendener
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  2. H. Schott
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Correspondence to R. A. Schwendener.

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Schwendener, R.A., Schott, H. Lipophilic 1-β-d-arabinofuranosyl cytosine derivatives in liposomal formulations for oral and parenteral antileukemic therapy in the murine L1210 leukemia model. J Cancer Res Clin Oncol 122, 723–726 (1996). https://doi.org/10.1007/BF01209119

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  • DOI: https://doi.org/10.1007/BF01209119

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