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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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