LIPOPHILIC 1-BETA-D-ARABINOFURANOSYL CYTOSINE DERIVATIVES IN LIPOSOMAL FORMULATIONS FOR ORAL AND PARENTERAL ANTILEUKEMIC THERAPY IN THE MURINE L1210 LEUKEMIA MODEL

The N-4-alkylcytosine arabinoside derivative N-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-beta-D-arabinofuranosylcytosine (AraC) that produce high antileukemi c 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 app lications with a total dose of 1 mmol/kg AraC-Ocd or Ocd-GroP-AraC. Co rresponding results were obtained after parenteral therapy on days 2 a nd 6 after tumor inoculation with five- to ten-fold lower concentratio ns of these two compounds. A comparable cytotoxic activity was found w ith the orally active AraC-5'-(n-stearyl phosphate). However, because of its strong hemolytic toxicity this derivative cannot be used for pa renteral therapy. Another AraC conjugate, which was modified with two long-chain hydrocarbons, the (1-octadecylglycero-3-phospho)-N-4-hexade cyl-AraC was, probably because of poor oral bioavailability, only acti ve when applied parenterally. The new lipophilic AraC derivatives AraC -Ocd and Ocd-GroP-AraC are compounds with a high potential for the ora l treatment of leukemias and possibly also of solid tumors.